OBJECTIVE To learn which factors influencing perineal integrity were modifiable by physicians and... more OBJECTIVE To learn which factors influencing perineal integrity were modifiable by physicians and pregnant women.
In all-atom simulations of lipid membranes, explicit hydrogen atoms contained in the hydrocarbon ... more In all-atom simulations of lipid membranes, explicit hydrogen atoms contained in the hydrocarbon region are described by a large number of degrees of freedom, although they convey only limited physical information. We propose an implicit-hydrogen model for saturated and monounsaturated acyl chains, aimed at complementing the all-atom CHARMM27 model for phospholipid headgroups. Torsional potentials and nonbonded parameters were fitted to reproduce experimental data and free energy surfaces of all-atom model systems. Comparative simulations of fluid-phase POPC bilayers were performed using the all-hydrogen force field and the present model. The hybrid model accelerates a typical bilayer simulation by about 50% while sacrificing a minimal amount of detail with respect to the fully atomistic description. In addition, the united-atom description is energetically compatible with all-atom CHARMM models, making it suitable for simulations of complex membrane systems.
A coarse-grain model for amphiphilic diblock copolymers is developed by fitting the required para... more A coarse-grain model for amphiphilic diblock copolymers is developed by fitting the required parameters to properties taken from all-atom molecular dynamics simulations and experimental data. Computations with the present coarse-grain model yield spontaneous self-assembly of a random system into membrane bilayers when the amphiphilic diblock copolymers have a lipid-like hydrophilic/hydrophobic ratio. The model semiquantitatively reproduces a number of experimental results that were not explicitly used in the parametrization. In particular, diblock polymers with the appropriate ratio of hydrophobic-hydrophilic segment lengths self-assemble into membranes whose hydrophobic thickness (determined from mass density profiles) and scaling with molecular weight are found to be in good agreement with the experiment.
Single crystals of NaHP 2 (sodium hydrogen dipalmitate) have been prepared from mixtures of NaP (... more Single crystals of NaHP 2 (sodium hydrogen dipalmitate) have been prepared from mixtures of NaP (sodium palmitate) and HP (palmitic acid) in ethanol. The phase compound crystallizes in the P2 1 /a space group, with a ) 9.906 Å, b ) 7.163 Å, c ) 45.580 Å, ) 92.78°, and 4 molecules per unit cell. The arrangement of the headgroups is unique among known soap and fatty acid structures by accommodating both hydrogen bonding and electrostatic interactions. Carboxylate and acid-like pairs couple perpendicular to the bilayer to accommodate a "short" hydrogen bond, and the sodium is shared among laterally adjacent carboxylate anions to create a pseudo-six-member ring, which adds to the crystal stability. Molecular dynamic (MD) simulations establish a set of interaction parameters to describe the structure and energetics of acid-carboxylate bonds, which accounts for the solid-state miscibility of HP and NaP. Infrared data, collected by ATR-FTIR on very pure, powdered NaH 2 P 3 , Na 2 H 3 P 5 , and NaHP 2 acid-soap standards reveal peculiar changes in the carbonyl and hydroxyl spectral regions. These spectra were analyzed on the basis of crystal structure and MD simulation data.
Phospholipid membranes play a key role in compartmentalization, as a medium for other species suc... more Phospholipid membranes play a key role in compartmentalization, as a medium for other species such as proteins to function, and as a structural scaffolding for cells. Recently interest is focusing on more active roles of phospholipids in the affecting the behavior of membrane proteins, ...
A series of first principles molecular dynamics and Monte Carlo simulations were carried out for ... more A series of first principles molecular dynamics and Monte Carlo simulations were carried out for liquid water to investigate the reproducibility of different sampling approaches. These simulations include Car−Parrinello molecular dynamics simulations using the program cpmd with ...
Three atomistic, empirical models for phosphatidylglycerol (PG) lipids are tested against structu... more Three atomistic, empirical models for phosphatidylglycerol (PG) lipids are tested against structural data in the crystal and liquid crystal states. Simulations of the anhydrous crystal of dimyristoylphosphatidylglycerol (DMPG) show that only the CHARMM force field describes the conformation and interactions of PG headgroups accurately. The other two models do not reproduce the native network of hydrogen bonds, suggesting the presence of biases in their conformational and nonbonded interaction properties. The CHARMM model is further validated in the biologically relevant liquid crystal phase by comparing experimental small-angle X-ray scattering spectra from DMPG unilamellar vesicles with data calculated from fluid bilayer simulations. The good agreement found in this model-free comparison implies that liquid crystal PG bilayers as described by CHARMM exhibit realistic bilayer thickness and lateral packing. Last, this model is used to simulate a fluid bilayer of palmitoyl-oleoyl-phosphatidylglycerol (POPG). The resulting view of POPG bilayer structure is at variance with that proposed previously based on simulations, in particular with respect to lateral packing of headgroups and the role of counterions.
An analysis of the structural and dynamical hydrogen bonding interactions at the lipid water inte... more An analysis of the structural and dynamical hydrogen bonding interactions at the lipid water interface from a 10 ns molecular dynamics simulation of a hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer is presented. We find that the average number of hydrogen bonds per lipid oxygen atom varies depending on its position within the lipid. Radial distribution functions are reported for water interacting with lipid oxygen, nitrogen, and phosphorus atoms, as well as for lipid-lipid interactions. The extent of inter-and intramolecular lipid-water-lipid hydrogen bond bridges is explored along with charge pair associations among headgroups of different lipid molecules. We also examine the hydrogen bonding dynamics of water at the lipid surface. A picture emerges of a sticky interface where water that is hydrogen bonded to lipid oxygen atoms diffuses slowly. Hydrogen bonds between water and the double bonded lipid oxygen atoms are longer lived than those to single bonded lipid oxygen atoms, and hydrogen bonds between water and the tail lipid oxygen atoms are longer lived than those to headgroup oxygen atoms. The implications of these results for lateral proton transfer at the interface are also discussed.
The recently introduced hills method (Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12562) is a powerfu... more The recently introduced hills method (Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12562) is a powerful tool to compute the multidimensional free energy surface of intrinsically concerted reactions. We have extended this method by focusing our attention on localizing the lowest free energy path that connects the stable reactant and product states. This path represents the most probable reaction mechanism, similar to the zero temperature intrinsic reaction coordinate, but also includes finite temperature effects. The transformation of the multidimensional problem to a one-dimensional reaction coordinate allows for accurate convergence of the free energy profile along the lowest free energy path using standard free energy methods. Here we apply the hills method, our lowest free energy path search algorithm, and umbrella sampling to the prototype S N 2 reaction. The hills method replaces the in many cases difficult problem of finding a good reaction coordinate with choosing relatively simple collective variables, such as the bond lengths of the broken and formed chemical bonds. The second part of the paper presents a guide to using the hills method, in which we test and fine-tune the method for optimal accuracy and efficiency using the umbrella sampling results as a reference. †
Gemini surfactants typically consist of two single-chain surfactants chemically linked by a space... more Gemini surfactants typically consist of two single-chain surfactants chemically linked by a spacer molecule. We report herein the results of fully atomistic molecular dynamics (MD) simulations of a series of Gemini surfactants: C s H 2s -R,ω-bis(C 12 H 25 N + (CH 3 ) 2 Cl -), at the air/water interface with s ) 3, 4, 6, 12, 14, and 16, at values of the initial surface area per surfactant A S ) 70 Å 2 , 77 Å 2 , 95 Å 2 , 151 Å 2 , 133 Å 2 , and 103 Å 2 , respectively. The A S values employed were obtained from surface tension and neutron reflection experiments at the respective cmc of each surfactant. The Gemini surfactant corresponding to s ) 3 was also simulated at A S ) 105 Å 2 , which is the experimentally derived value of surface area per surfactant at 1/10th of cmc. Only the surfactants with s ) 12 and 14 and the surfactant with s ) 3 at A S ) 105 A 2 gave a stable monolayer at the air/water interface. In other cases, we observe movement of some surfactant molecules from the air/ water interface into the aqueous phase, resulting in a stable primary monolayer of surfactants at the air/water interface and a small concentration of surfactant molecules below it. The latter form aggregates, with their hydrophobic chains in the core. The density profiles along the normal to the interface are compared with the ones obtained from neutron reflection experiments. The MD simulations confirm the bending of the spacer toward the hydrophobic chains as the spacer length is increased and the spacer becomes more hydrophobic. The simulations have helped to shed light on the low-resolution picture which emerges from experimental analyses.
The effect of membrane proteins and peptides on their surrounding lipids is crucial for the struc... more The effect of membrane proteins and peptides on their surrounding lipids is crucial for the structure, dynamics, and function of complex biological membranes as well as the interplay between membrane proteins and their environment. Here, we present a study of the influence of the transmembrane pore region of an ion channel on the physical properties of a phospholipid bilayer. We performed multinanosecond molecular dynamics simulations of the pore-forming aggregate of R-helical transmembrane peptides, which constitutes a model for the channel region of the nicotinic acetylcholine receptor, inserted in a simple lipid bilayer at conditions similar to those of the recent NMR experiments et al. Nature Struct. Biol. 1999, 6, 374]. The results obtained are compared with simulations of the pure lipid bilayer membrane. In particular, we consider here the simplest possible model membrane: a fully hydrated dimyristoyl-sn-glycerophosphocholine lipid bilayer, which is in the biologically relevant fluid lamellar phase at room temperature. Our analysis reveals that the peptides affect the properties of the lipid bilayer in several ways: (1) the bilayer thickness increases, (2) the number of gauche defects of the hydrocarbon chains decreases, (3) the orientational order of the hydrocarbon chains increases, (4) the orientational probability distribution of the lipid headgroup dipole moments becomes broader (more disordered), and (5) the lipid headgroup dipole moments are on average more oriented toward the water phase. Some of these effects depend on the specific properties of the case studied, such as the hydrophobic length of the bundle and the charges at the interface. Interestingly, the pore does not affect the two different sides of the membrane in the same way.
We use molecular dynamics simulations to investigate the effects of halothane, a volatile anesthe... more We use molecular dynamics simulations to investigate the effects of halothane, a volatile anesthetic, and hexafluoroethane (HFE), its nonimmobilizer analogue, on the physical properties of a fully hydrated polyunsaturated (1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine) lipid bilayer in the liquid crystalline fluid lamellar phase, L R . In addition, we discuss the results obtained comparing them to previous studies on saturated lipid bilayers with the same solutes. At the analyzed concentration (25% mole fraction), the halothane molecules are located preferentially near the upper part of the lipid acyl chains, while the HFE molecules prefer the hydrocarbon chains and methyl trough region. In the case of halothane in the polyunsaturated lipid bilayer, there is an additional density maximum at the membrane center not observed in saturated lipids. The subtle effect of the solutes on the structural properties of the highly unsaturated lipid bilayer and the properties of the membrane interior is somewhat different from that observed for saturated lipids. Here, these differences are interpreted in terms of the unique properties of the polyunsaturated lipid bilayers. The effect of anesthetic molecules on the electrostatic properties of the membrane interface is similar for saturated and polyunsaturated lipid bilayers and is characterized by a change in the most probable orientation of the lipid headgroup dipoles, which point toward the membrane interior for halothane and are basically unchanged for HFE, i.e., point toward the water phase. The different distributions of anesthetic and nonimmobilizer molecules within the lipid bilayer systems seem to be a generic feature in simple models of biological membranes and are similar to those observed in systems with saturated lipids. Since polyunsaturated and other unsaturated lipids are ubiquitous in cell membranes, it is plausible to generalize these features to the more complex biological membranes.
Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics method... more Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics methods, we address the relationship between molecular conformation and the biomedical function of arylamide polymers. Specifically, we have developed new torsional parameters for a class of these polymers and applied them in a study of the interaction between a representative arylamide and one of its biomedical targets, the anticoagulant drug heparin. Our main finding is that the torsional barrier of a C aromatic -C carbonyl bond increases significantly upon addition of an o-OCH 2 CH 2 NH 3 + substituent on the benzene ring. Our molecular dynamics studies that are based on the original general AMBER force field (GAFF) and GAFF modified to include our newly developed torsional parameters show that the binding mechanism between the arylamide and heparin is very sensitive to the choice of torsional potentials. Ab initio molecular dynamics simulation of the arylamide independently confirms the degree of flexibility we obtain by classical molecular dynamics when newly developed torsional potentials are used. † Part of the special issue "Michael L. Klein Festschrift".
The self-assembly of cyclic D,L-R-peptides into hollow nanotubes is a crucial mechanistic step in... more The self-assembly of cyclic D,L-R-peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo [(-L-Trp-D-N-MeLeu-) 4 -] 2 and cyclo [(-L-Trp-D-Leu-) 4 -] 2 subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the and ψ dihedral angles of a single uncapped ring in nonane lie in the -sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers.
The structure of linear water wires with an excess proton was studied at room temperature using a... more The structure of linear water wires with an excess proton was studied at room temperature using ab initio path integral molecular dynamics. The ab initio Car-Parrinello (CP) methodology employed the density functional theory (DFT) description of the electronic ...
Hole transfer processes between base pairs in natural DNA and size-expanded DNA (xDNA) are studie... more Hole transfer processes between base pairs in natural DNA and size-expanded DNA (xDNA) are studied and compared, by means of an accurate first principles evaluation of the effective electronic couplings (also known as transfer integrals), in order to assess the effect of the base augmentation on the efficiency of charge transport through double-stranded DNA. According to our results, the size expansion increases the average electronic coupling, and thus the CT rate, with potential implications in molecular biology and in the implementation of molecular nanoelectronics. Our analysis shows that the effect of the nucleobase expansion on the charge-transfer (CT) rate is sensitive to the sequence of base pairs. Furthermore, we find that conformational variability is an important factor for the modulation of the CT rate. From a theoretical point of view, this work offers a contribution to the CT chemistry in π-stacked arrays. Indeed, we compare our methodology against other standard computational frameworks that have been adopted to tackle the problem of CT in DNA, and unravel basic principles that should be accounted for in selecting an appropriate theoretical level.
The structural and dynamical properties of the four R-helix bundle Due Ferri 1, which is a generi... more The structural and dynamical properties of the four R-helix bundle Due Ferri 1, which is a generic mimic of diiron proteins, have been explored using density functional theory (DFT) based and hybrid quantum/classical molecular dynamics (QM/MM) simulations. Four quantum mechanical (QM) representations of the active site have been employed in order to systematically assess the role of first and second shell interactions: (a) a 66-atom fragment of the active site comprising only first shell ligands, (b and c) two systems (78 and 86 atoms) containing different second shell hydrogen bonds, and (d) a 98-atom model including both the first and second shell residues. Two QM/MM partitioning schemes have been explored in order to explicitly consider the role of the whole protein environment: (a) a 54-QM-atom model in which only the first shell ligands are described at the DFT level, while the rest of the protein environment is taken into account at the MM level and (b) a 68-QM-atom model in which the first shell ligands plus a second shell hydrogen bond network is considered at the DFT level. All of the calculations confirm the highly flexible nature of the carboxylatebridged binuclear motif and demonstrate the importance of the whole protein environment in stabilizing the hydrogen bond networks that surround the active site. The present QM/MM approach allows for the identification of key factors governing the stability/reactivity of the active site and thus provides unique insights that can be exploited for the future tailoring of new highly selective biomimetic enzymatic compounds.
Dinuclear azole-bridged Pt compounds bind to DNA helices, forming intrastrand crosslinks between ... more Dinuclear azole-bridged Pt compounds bind to DNA helices, forming intrastrand crosslinks between adjacent guanines in a similar way to cisplatin. Their cytotoxic profile is, however, different from that of first and second generation Pt drugs in that they lack cross resistance in cisplatin-resistant cell lines. In contrast to cisplatin, which induces a large kink in DNA duplex, structural NMR studies and molecular dynamics simulations have shown that azole-bridged diplatinum compounds induce only small structural changes in double-stranded DNA. These structural differences have been invoked to explain the different cytotoxic profile of these compounds. Here, we show that in addition to the small structural changes in DNA, dinuclear Pt compounds also affect DNA minor groove flexibility in a different way than cisplatin. Free-energy calculations on azole-bridged diplatinum DNA adducts reveal that opening of the minor groove requires a higher free-energy cost (DeltaG ~ 7-15 kcal/mol) than in the corresponding cisplatin-DNA adduct (DeltaG ~ 0 kcal/mol). This could prevent minor groove binding proteins from binding to diplatinum-DNA adducts thus leading to a different cellular response than cisplatin and possibly decreasing the activity of excision repair enzymes. Although the development of drug resistance is a highly complex mechanism, our findings provide an additional rationale for the improved cytotoxic activity of these compounds in cell lines resistant to cisplatin.
We present the results of molecular dynamics (MD) simulations of coarse-grain 1,2-di-n-alkanoyl-s... more We present the results of molecular dynamics (MD) simulations of coarse-grain 1,2-di-n-alkanoyl-sn-glycero-3-phosphocholine Langmuir monolayer systems. Two separate alkanoyl length lipids are considered. Surface pressure versus area per lipid isotherms are obtained for both lipid species and are compared to experimental and previous atomistic MD work. The short-tail lipid cannot support a surface pressure above that expected at the critical micelle concentration. In contrast, the long-tail lipid is studied in the metastable regime of slightly negative surface tension. At still higher surface coverage, the interface is destabilized, leading to monolayer collapse via a novel mechanism in which a charge-neutralizing bridge of zwitterionic headgroups is established to transport lipids across the alkanoyl region. Area per lipid compression simulations are also performed at constant lipid number to demonstrate that the observed instabilities are generic.
OBJECTIVE To learn which factors influencing perineal integrity were modifiable by physicians and... more OBJECTIVE To learn which factors influencing perineal integrity were modifiable by physicians and pregnant women.
In all-atom simulations of lipid membranes, explicit hydrogen atoms contained in the hydrocarbon ... more In all-atom simulations of lipid membranes, explicit hydrogen atoms contained in the hydrocarbon region are described by a large number of degrees of freedom, although they convey only limited physical information. We propose an implicit-hydrogen model for saturated and monounsaturated acyl chains, aimed at complementing the all-atom CHARMM27 model for phospholipid headgroups. Torsional potentials and nonbonded parameters were fitted to reproduce experimental data and free energy surfaces of all-atom model systems. Comparative simulations of fluid-phase POPC bilayers were performed using the all-hydrogen force field and the present model. The hybrid model accelerates a typical bilayer simulation by about 50% while sacrificing a minimal amount of detail with respect to the fully atomistic description. In addition, the united-atom description is energetically compatible with all-atom CHARMM models, making it suitable for simulations of complex membrane systems.
A coarse-grain model for amphiphilic diblock copolymers is developed by fitting the required para... more A coarse-grain model for amphiphilic diblock copolymers is developed by fitting the required parameters to properties taken from all-atom molecular dynamics simulations and experimental data. Computations with the present coarse-grain model yield spontaneous self-assembly of a random system into membrane bilayers when the amphiphilic diblock copolymers have a lipid-like hydrophilic/hydrophobic ratio. The model semiquantitatively reproduces a number of experimental results that were not explicitly used in the parametrization. In particular, diblock polymers with the appropriate ratio of hydrophobic-hydrophilic segment lengths self-assemble into membranes whose hydrophobic thickness (determined from mass density profiles) and scaling with molecular weight are found to be in good agreement with the experiment.
Single crystals of NaHP 2 (sodium hydrogen dipalmitate) have been prepared from mixtures of NaP (... more Single crystals of NaHP 2 (sodium hydrogen dipalmitate) have been prepared from mixtures of NaP (sodium palmitate) and HP (palmitic acid) in ethanol. The phase compound crystallizes in the P2 1 /a space group, with a ) 9.906 Å, b ) 7.163 Å, c ) 45.580 Å, ) 92.78°, and 4 molecules per unit cell. The arrangement of the headgroups is unique among known soap and fatty acid structures by accommodating both hydrogen bonding and electrostatic interactions. Carboxylate and acid-like pairs couple perpendicular to the bilayer to accommodate a "short" hydrogen bond, and the sodium is shared among laterally adjacent carboxylate anions to create a pseudo-six-member ring, which adds to the crystal stability. Molecular dynamic (MD) simulations establish a set of interaction parameters to describe the structure and energetics of acid-carboxylate bonds, which accounts for the solid-state miscibility of HP and NaP. Infrared data, collected by ATR-FTIR on very pure, powdered NaH 2 P 3 , Na 2 H 3 P 5 , and NaHP 2 acid-soap standards reveal peculiar changes in the carbonyl and hydroxyl spectral regions. These spectra were analyzed on the basis of crystal structure and MD simulation data.
Phospholipid membranes play a key role in compartmentalization, as a medium for other species suc... more Phospholipid membranes play a key role in compartmentalization, as a medium for other species such as proteins to function, and as a structural scaffolding for cells. Recently interest is focusing on more active roles of phospholipids in the affecting the behavior of membrane proteins, ...
A series of first principles molecular dynamics and Monte Carlo simulations were carried out for ... more A series of first principles molecular dynamics and Monte Carlo simulations were carried out for liquid water to investigate the reproducibility of different sampling approaches. These simulations include Car−Parrinello molecular dynamics simulations using the program cpmd with ...
Three atomistic, empirical models for phosphatidylglycerol (PG) lipids are tested against structu... more Three atomistic, empirical models for phosphatidylglycerol (PG) lipids are tested against structural data in the crystal and liquid crystal states. Simulations of the anhydrous crystal of dimyristoylphosphatidylglycerol (DMPG) show that only the CHARMM force field describes the conformation and interactions of PG headgroups accurately. The other two models do not reproduce the native network of hydrogen bonds, suggesting the presence of biases in their conformational and nonbonded interaction properties. The CHARMM model is further validated in the biologically relevant liquid crystal phase by comparing experimental small-angle X-ray scattering spectra from DMPG unilamellar vesicles with data calculated from fluid bilayer simulations. The good agreement found in this model-free comparison implies that liquid crystal PG bilayers as described by CHARMM exhibit realistic bilayer thickness and lateral packing. Last, this model is used to simulate a fluid bilayer of palmitoyl-oleoyl-phosphatidylglycerol (POPG). The resulting view of POPG bilayer structure is at variance with that proposed previously based on simulations, in particular with respect to lateral packing of headgroups and the role of counterions.
An analysis of the structural and dynamical hydrogen bonding interactions at the lipid water inte... more An analysis of the structural and dynamical hydrogen bonding interactions at the lipid water interface from a 10 ns molecular dynamics simulation of a hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer is presented. We find that the average number of hydrogen bonds per lipid oxygen atom varies depending on its position within the lipid. Radial distribution functions are reported for water interacting with lipid oxygen, nitrogen, and phosphorus atoms, as well as for lipid-lipid interactions. The extent of inter-and intramolecular lipid-water-lipid hydrogen bond bridges is explored along with charge pair associations among headgroups of different lipid molecules. We also examine the hydrogen bonding dynamics of water at the lipid surface. A picture emerges of a sticky interface where water that is hydrogen bonded to lipid oxygen atoms diffuses slowly. Hydrogen bonds between water and the double bonded lipid oxygen atoms are longer lived than those to single bonded lipid oxygen atoms, and hydrogen bonds between water and the tail lipid oxygen atoms are longer lived than those to headgroup oxygen atoms. The implications of these results for lateral proton transfer at the interface are also discussed.
The recently introduced hills method (Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12562) is a powerfu... more The recently introduced hills method (Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12562) is a powerful tool to compute the multidimensional free energy surface of intrinsically concerted reactions. We have extended this method by focusing our attention on localizing the lowest free energy path that connects the stable reactant and product states. This path represents the most probable reaction mechanism, similar to the zero temperature intrinsic reaction coordinate, but also includes finite temperature effects. The transformation of the multidimensional problem to a one-dimensional reaction coordinate allows for accurate convergence of the free energy profile along the lowest free energy path using standard free energy methods. Here we apply the hills method, our lowest free energy path search algorithm, and umbrella sampling to the prototype S N 2 reaction. The hills method replaces the in many cases difficult problem of finding a good reaction coordinate with choosing relatively simple collective variables, such as the bond lengths of the broken and formed chemical bonds. The second part of the paper presents a guide to using the hills method, in which we test and fine-tune the method for optimal accuracy and efficiency using the umbrella sampling results as a reference. †
Gemini surfactants typically consist of two single-chain surfactants chemically linked by a space... more Gemini surfactants typically consist of two single-chain surfactants chemically linked by a spacer molecule. We report herein the results of fully atomistic molecular dynamics (MD) simulations of a series of Gemini surfactants: C s H 2s -R,ω-bis(C 12 H 25 N + (CH 3 ) 2 Cl -), at the air/water interface with s ) 3, 4, 6, 12, 14, and 16, at values of the initial surface area per surfactant A S ) 70 Å 2 , 77 Å 2 , 95 Å 2 , 151 Å 2 , 133 Å 2 , and 103 Å 2 , respectively. The A S values employed were obtained from surface tension and neutron reflection experiments at the respective cmc of each surfactant. The Gemini surfactant corresponding to s ) 3 was also simulated at A S ) 105 Å 2 , which is the experimentally derived value of surface area per surfactant at 1/10th of cmc. Only the surfactants with s ) 12 and 14 and the surfactant with s ) 3 at A S ) 105 A 2 gave a stable monolayer at the air/water interface. In other cases, we observe movement of some surfactant molecules from the air/ water interface into the aqueous phase, resulting in a stable primary monolayer of surfactants at the air/water interface and a small concentration of surfactant molecules below it. The latter form aggregates, with their hydrophobic chains in the core. The density profiles along the normal to the interface are compared with the ones obtained from neutron reflection experiments. The MD simulations confirm the bending of the spacer toward the hydrophobic chains as the spacer length is increased and the spacer becomes more hydrophobic. The simulations have helped to shed light on the low-resolution picture which emerges from experimental analyses.
The effect of membrane proteins and peptides on their surrounding lipids is crucial for the struc... more The effect of membrane proteins and peptides on their surrounding lipids is crucial for the structure, dynamics, and function of complex biological membranes as well as the interplay between membrane proteins and their environment. Here, we present a study of the influence of the transmembrane pore region of an ion channel on the physical properties of a phospholipid bilayer. We performed multinanosecond molecular dynamics simulations of the pore-forming aggregate of R-helical transmembrane peptides, which constitutes a model for the channel region of the nicotinic acetylcholine receptor, inserted in a simple lipid bilayer at conditions similar to those of the recent NMR experiments et al. Nature Struct. Biol. 1999, 6, 374]. The results obtained are compared with simulations of the pure lipid bilayer membrane. In particular, we consider here the simplest possible model membrane: a fully hydrated dimyristoyl-sn-glycerophosphocholine lipid bilayer, which is in the biologically relevant fluid lamellar phase at room temperature. Our analysis reveals that the peptides affect the properties of the lipid bilayer in several ways: (1) the bilayer thickness increases, (2) the number of gauche defects of the hydrocarbon chains decreases, (3) the orientational order of the hydrocarbon chains increases, (4) the orientational probability distribution of the lipid headgroup dipole moments becomes broader (more disordered), and (5) the lipid headgroup dipole moments are on average more oriented toward the water phase. Some of these effects depend on the specific properties of the case studied, such as the hydrophobic length of the bundle and the charges at the interface. Interestingly, the pore does not affect the two different sides of the membrane in the same way.
We use molecular dynamics simulations to investigate the effects of halothane, a volatile anesthe... more We use molecular dynamics simulations to investigate the effects of halothane, a volatile anesthetic, and hexafluoroethane (HFE), its nonimmobilizer analogue, on the physical properties of a fully hydrated polyunsaturated (1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine) lipid bilayer in the liquid crystalline fluid lamellar phase, L R . In addition, we discuss the results obtained comparing them to previous studies on saturated lipid bilayers with the same solutes. At the analyzed concentration (25% mole fraction), the halothane molecules are located preferentially near the upper part of the lipid acyl chains, while the HFE molecules prefer the hydrocarbon chains and methyl trough region. In the case of halothane in the polyunsaturated lipid bilayer, there is an additional density maximum at the membrane center not observed in saturated lipids. The subtle effect of the solutes on the structural properties of the highly unsaturated lipid bilayer and the properties of the membrane interior is somewhat different from that observed for saturated lipids. Here, these differences are interpreted in terms of the unique properties of the polyunsaturated lipid bilayers. The effect of anesthetic molecules on the electrostatic properties of the membrane interface is similar for saturated and polyunsaturated lipid bilayers and is characterized by a change in the most probable orientation of the lipid headgroup dipoles, which point toward the membrane interior for halothane and are basically unchanged for HFE, i.e., point toward the water phase. The different distributions of anesthetic and nonimmobilizer molecules within the lipid bilayer systems seem to be a generic feature in simple models of biological membranes and are similar to those observed in systems with saturated lipids. Since polyunsaturated and other unsaturated lipids are ubiquitous in cell membranes, it is plausible to generalize these features to the more complex biological membranes.
Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics method... more Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics methods, we address the relationship between molecular conformation and the biomedical function of arylamide polymers. Specifically, we have developed new torsional parameters for a class of these polymers and applied them in a study of the interaction between a representative arylamide and one of its biomedical targets, the anticoagulant drug heparin. Our main finding is that the torsional barrier of a C aromatic -C carbonyl bond increases significantly upon addition of an o-OCH 2 CH 2 NH 3 + substituent on the benzene ring. Our molecular dynamics studies that are based on the original general AMBER force field (GAFF) and GAFF modified to include our newly developed torsional parameters show that the binding mechanism between the arylamide and heparin is very sensitive to the choice of torsional potentials. Ab initio molecular dynamics simulation of the arylamide independently confirms the degree of flexibility we obtain by classical molecular dynamics when newly developed torsional potentials are used. † Part of the special issue "Michael L. Klein Festschrift".
The self-assembly of cyclic D,L-R-peptides into hollow nanotubes is a crucial mechanistic step in... more The self-assembly of cyclic D,L-R-peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo [(-L-Trp-D-N-MeLeu-) 4 -] 2 and cyclo [(-L-Trp-D-Leu-) 4 -] 2 subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the and ψ dihedral angles of a single uncapped ring in nonane lie in the -sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers.
The structure of linear water wires with an excess proton was studied at room temperature using a... more The structure of linear water wires with an excess proton was studied at room temperature using ab initio path integral molecular dynamics. The ab initio Car-Parrinello (CP) methodology employed the density functional theory (DFT) description of the electronic ...
Hole transfer processes between base pairs in natural DNA and size-expanded DNA (xDNA) are studie... more Hole transfer processes between base pairs in natural DNA and size-expanded DNA (xDNA) are studied and compared, by means of an accurate first principles evaluation of the effective electronic couplings (also known as transfer integrals), in order to assess the effect of the base augmentation on the efficiency of charge transport through double-stranded DNA. According to our results, the size expansion increases the average electronic coupling, and thus the CT rate, with potential implications in molecular biology and in the implementation of molecular nanoelectronics. Our analysis shows that the effect of the nucleobase expansion on the charge-transfer (CT) rate is sensitive to the sequence of base pairs. Furthermore, we find that conformational variability is an important factor for the modulation of the CT rate. From a theoretical point of view, this work offers a contribution to the CT chemistry in π-stacked arrays. Indeed, we compare our methodology against other standard computational frameworks that have been adopted to tackle the problem of CT in DNA, and unravel basic principles that should be accounted for in selecting an appropriate theoretical level.
The structural and dynamical properties of the four R-helix bundle Due Ferri 1, which is a generi... more The structural and dynamical properties of the four R-helix bundle Due Ferri 1, which is a generic mimic of diiron proteins, have been explored using density functional theory (DFT) based and hybrid quantum/classical molecular dynamics (QM/MM) simulations. Four quantum mechanical (QM) representations of the active site have been employed in order to systematically assess the role of first and second shell interactions: (a) a 66-atom fragment of the active site comprising only first shell ligands, (b and c) two systems (78 and 86 atoms) containing different second shell hydrogen bonds, and (d) a 98-atom model including both the first and second shell residues. Two QM/MM partitioning schemes have been explored in order to explicitly consider the role of the whole protein environment: (a) a 54-QM-atom model in which only the first shell ligands are described at the DFT level, while the rest of the protein environment is taken into account at the MM level and (b) a 68-QM-atom model in which the first shell ligands plus a second shell hydrogen bond network is considered at the DFT level. All of the calculations confirm the highly flexible nature of the carboxylatebridged binuclear motif and demonstrate the importance of the whole protein environment in stabilizing the hydrogen bond networks that surround the active site. The present QM/MM approach allows for the identification of key factors governing the stability/reactivity of the active site and thus provides unique insights that can be exploited for the future tailoring of new highly selective biomimetic enzymatic compounds.
Dinuclear azole-bridged Pt compounds bind to DNA helices, forming intrastrand crosslinks between ... more Dinuclear azole-bridged Pt compounds bind to DNA helices, forming intrastrand crosslinks between adjacent guanines in a similar way to cisplatin. Their cytotoxic profile is, however, different from that of first and second generation Pt drugs in that they lack cross resistance in cisplatin-resistant cell lines. In contrast to cisplatin, which induces a large kink in DNA duplex, structural NMR studies and molecular dynamics simulations have shown that azole-bridged diplatinum compounds induce only small structural changes in double-stranded DNA. These structural differences have been invoked to explain the different cytotoxic profile of these compounds. Here, we show that in addition to the small structural changes in DNA, dinuclear Pt compounds also affect DNA minor groove flexibility in a different way than cisplatin. Free-energy calculations on azole-bridged diplatinum DNA adducts reveal that opening of the minor groove requires a higher free-energy cost (DeltaG ~ 7-15 kcal/mol) than in the corresponding cisplatin-DNA adduct (DeltaG ~ 0 kcal/mol). This could prevent minor groove binding proteins from binding to diplatinum-DNA adducts thus leading to a different cellular response than cisplatin and possibly decreasing the activity of excision repair enzymes. Although the development of drug resistance is a highly complex mechanism, our findings provide an additional rationale for the improved cytotoxic activity of these compounds in cell lines resistant to cisplatin.
We present the results of molecular dynamics (MD) simulations of coarse-grain 1,2-di-n-alkanoyl-s... more We present the results of molecular dynamics (MD) simulations of coarse-grain 1,2-di-n-alkanoyl-sn-glycero-3-phosphocholine Langmuir monolayer systems. Two separate alkanoyl length lipids are considered. Surface pressure versus area per lipid isotherms are obtained for both lipid species and are compared to experimental and previous atomistic MD work. The short-tail lipid cannot support a surface pressure above that expected at the critical micelle concentration. In contrast, the long-tail lipid is studied in the metastable regime of slightly negative surface tension. At still higher surface coverage, the interface is destabilized, leading to monolayer collapse via a novel mechanism in which a charge-neutralizing bridge of zwitterionic headgroups is established to transport lipids across the alkanoyl region. Area per lipid compression simulations are also performed at constant lipid number to demonstrate that the observed instabilities are generic.
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Papers by Michael Klein