Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of am... more Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of amyloidb peptide (Ab) into amyloid fibrils. From the results of several studies it is believed that caffeine can prevent the development of Alzheimer’s disease. However, the molecular mechanism of the therapeutic potential of caffeine is largely unknown. In our study, we have investigated the effect of caffeine on the aggregation of amyloid-b derived switch-peptide by varying the stoichiometric ratio of caffeine to peptide. Our molecular dynamics study of peptides in pure water show the formation of a b-sheet conformation, which is prevented to a large extent in the presence of a 10 : 1 or greater ratio of caffeine to peptide. The experimental results demonstrate that caffeine can inhibit the formation of b-sheets by interacting with the peptide aromatic moiety. A detailed molecular dynamics analysis of the inhibition of peptide aggregation by caffeine further revealed that caffeine molecu...
Abstract Hydrophobic effect is one of the major driving forces in biomolecular interactions. Biol... more Abstract Hydrophobic effect is one of the major driving forces in biomolecular interactions. Biological molecules such as proteins and nucleic acids contain numerous hydrophobic components, and their interactions play critical roles in protein folding-unfolding and protein aggregation. In our study, we have carried out molecular dynamics simulation to understand the effect of caffeine on hydrophobic aggregation of di-t-butyl-methane (DTBM) molecules. For this we consider aqueous solutions of a regime of caffeine:DTBM stoichiometric ratios. From the calculations of site-site radial distribution functions followed by the coordination number analyses and spatial distribution plots we have observed the disruption of hydrophobic moieties of DTBM aggregates in 10:1 or more stoichiometric ratio of caffeine:DTBM systems. Calculations of binding affinities, preferential interaction parameters, and effect of caffeine cluster's size on aggregation show that though the binding affinity of DTBM with itself is more when compared to that of caffeine-DTBM, with increasing caffeine number the former decreases. On the other hand, in the presence of higher number of caffeine molecules the formation of caffeine clusters takes place and these caffeine clusters form a hydrophobic environment in which DTBM molecule is encapsulated. The presence of a significant number of water molecules in this confinement also ensures the hydration of DTBM. Moreover, these caffeine clusters also act as barriers and physically block the DTBM molecules to interact with the like molecules leading to a disruption of DTBM aggregates in caffeine solution.
π → π stacking interaction takes place prior to aggregation as the early event of amyloid aggrega... more π → π stacking interaction takes place prior to aggregation as the early event of amyloid aggregation of amyloidogenic peptides.
The effect of salt concentration on association properties of caffeine molecule was investigated ... more The effect of salt concentration on association properties of caffeine molecule was investigated by employing molecular dynamics simulations in isothermal-isobaric ensemble of eight caffeine molecules in pure water and three different salt (NaCl) concentrations, at 300 K temperature and 1 atm pressure. The concentration of caffeine was taken almost at the solubility limit. With increasing salt concentration, we observe enhancement of first peak height and appearance of a second peak in the caffeine-caffeine distribution function. Furthermore, our calculated solvent accessible area values and cluster structure analyses suggest formation of higher order caffeine cluster on addition of salt. The calculated hydrogen bond properties reveal that there is a modest decrease in the average number of water-caffeine hydrogen bonds on addition of NaCl salt. Also observed are: (i) decrease in probability of salt contact ion pair as well as decrease in the solvent separated ion pair formation with increasing salt concentration, (ii) a modest second shell collapse in the water structure, and (iii) dehydration of hydrophobic atomic sites of caffeine on addition of NaCl.
It is challenging to determine the structures of protein fibrils such as amyloids. In principle, ... more It is challenging to determine the structures of protein fibrils such as amyloids. In principle, Molecular Dynamics (MD) modeling can aid experiments, but normal MD has been impractical for these large multi-molecules. Here, we show that MELD accelerated MD (MELD x MD) can give amyloid structures from limited data. Five long-chain fibril structures are accurately predicted from NMR and Solid State NMR (SSNMR) data. Ten short-chain fibril structures are accurately predicted from more limited restraints information derived from the knowledge of strand directions. Although the present study only tests against structure predictions – which are the most detailed form of validation currently available – the main promise of this physical approach is ultimately in going beyond structures to also give mechanical properties, conformational ensembles, and relative stabilities.
Alzheimer's disease is a neurodegenerative disease caused due to aggregation of Aβ peptides i... more Alzheimer's disease is a neurodegenerative disease caused due to aggregation of Aβ peptides in the brain tissues. Recently, several studies on Alzheimer's disease transgenic mice have shown the effect of caffeine in significantly reducing the Aβ amyloid level in their brains. However, the mechanism and mode of caffeine action on amyloid aggregation are not known. Therefore, in this study, we have carried out molecular dynamics simulation of five amyloid forming Aβ16-22 peptide in pure water and in a regime of caffeine solutions, with different caffeine : peptide stoichiometric ratios. The secondary structure analyses of peptides in pure water show the formation of β-sheet conformation, whereas on addition of caffeine these ordered conformation become negligible. Radial distribution function, contact map, nonbonding interaction energy, hydrogen bonding, potential of mean force and hydration analyses show less inter-peptide interaction in presence of caffeine, and the effect i...
To examine the molecular level understanding of temperature induced self-association of caffeine ... more To examine the molecular level understanding of temperature induced self-association of caffeine molecules in aqueous solution both in the presence and absence of salt NaCl, we have performed long MD simulations at a regime of temperatures ranging from 275 to 350 K with a temperature difference of 25 K. The calculations of different site-site radial distribution functions followed by coordination number analyses, the calculations of preferential interaction parameters, solvent accessible surface area, and cluster structure analyses show a depletion in the caffeine association propensity with increasing temperature. We have also observed the salting out effect of caffeine molecules in salt solution. The simultaneous presence of polar and nonpolar groups in a caffeine molecule leads to anisotropic hydration. Specifically, the hydration tendency of caffeine hydrophobic sites increases with increasing temperature, while hydrophilic sites tend to be less hydrated. This leads to a decrease in caffeine association. In accordance with some experimental studies on thermodynamics of caffeine association, we have also observed enthalpy driven association in pure water. But the presence of salt leads to entropy driven association specifically at higher temperature. This is due to the relatively stronger interactions of salt ions with caffeine at higher temperature.
Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of am... more Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of amyloidb peptide (Ab) into amyloid fibrils. From the results of several studies it is believed that caffeine can prevent the development of Alzheimer’s disease. However, the molecular mechanism of the therapeutic potential of caffeine is largely unknown. In our study, we have investigated the effect of caffeine on the aggregation of amyloid-b derived switch-peptide by varying the stoichiometric ratio of caffeine to peptide. Our molecular dynamics study of peptides in pure water show the formation of a b-sheet conformation, which is prevented to a large extent in the presence of a 10 : 1 or greater ratio of caffeine to peptide. The experimental results demonstrate that caffeine can inhibit the formation of b-sheets by interacting with the peptide aromatic moiety. A detailed molecular dynamics analysis of the inhibition of peptide aggregation by caffeine further revealed that caffeine molecu...
Abstract Hydrophobic effect is one of the major driving forces in biomolecular interactions. Biol... more Abstract Hydrophobic effect is one of the major driving forces in biomolecular interactions. Biological molecules such as proteins and nucleic acids contain numerous hydrophobic components, and their interactions play critical roles in protein folding-unfolding and protein aggregation. In our study, we have carried out molecular dynamics simulation to understand the effect of caffeine on hydrophobic aggregation of di-t-butyl-methane (DTBM) molecules. For this we consider aqueous solutions of a regime of caffeine:DTBM stoichiometric ratios. From the calculations of site-site radial distribution functions followed by the coordination number analyses and spatial distribution plots we have observed the disruption of hydrophobic moieties of DTBM aggregates in 10:1 or more stoichiometric ratio of caffeine:DTBM systems. Calculations of binding affinities, preferential interaction parameters, and effect of caffeine cluster's size on aggregation show that though the binding affinity of DTBM with itself is more when compared to that of caffeine-DTBM, with increasing caffeine number the former decreases. On the other hand, in the presence of higher number of caffeine molecules the formation of caffeine clusters takes place and these caffeine clusters form a hydrophobic environment in which DTBM molecule is encapsulated. The presence of a significant number of water molecules in this confinement also ensures the hydration of DTBM. Moreover, these caffeine clusters also act as barriers and physically block the DTBM molecules to interact with the like molecules leading to a disruption of DTBM aggregates in caffeine solution.
π → π stacking interaction takes place prior to aggregation as the early event of amyloid aggrega... more π → π stacking interaction takes place prior to aggregation as the early event of amyloid aggregation of amyloidogenic peptides.
The effect of salt concentration on association properties of caffeine molecule was investigated ... more The effect of salt concentration on association properties of caffeine molecule was investigated by employing molecular dynamics simulations in isothermal-isobaric ensemble of eight caffeine molecules in pure water and three different salt (NaCl) concentrations, at 300 K temperature and 1 atm pressure. The concentration of caffeine was taken almost at the solubility limit. With increasing salt concentration, we observe enhancement of first peak height and appearance of a second peak in the caffeine-caffeine distribution function. Furthermore, our calculated solvent accessible area values and cluster structure analyses suggest formation of higher order caffeine cluster on addition of salt. The calculated hydrogen bond properties reveal that there is a modest decrease in the average number of water-caffeine hydrogen bonds on addition of NaCl salt. Also observed are: (i) decrease in probability of salt contact ion pair as well as decrease in the solvent separated ion pair formation with increasing salt concentration, (ii) a modest second shell collapse in the water structure, and (iii) dehydration of hydrophobic atomic sites of caffeine on addition of NaCl.
It is challenging to determine the structures of protein fibrils such as amyloids. In principle, ... more It is challenging to determine the structures of protein fibrils such as amyloids. In principle, Molecular Dynamics (MD) modeling can aid experiments, but normal MD has been impractical for these large multi-molecules. Here, we show that MELD accelerated MD (MELD x MD) can give amyloid structures from limited data. Five long-chain fibril structures are accurately predicted from NMR and Solid State NMR (SSNMR) data. Ten short-chain fibril structures are accurately predicted from more limited restraints information derived from the knowledge of strand directions. Although the present study only tests against structure predictions – which are the most detailed form of validation currently available – the main promise of this physical approach is ultimately in going beyond structures to also give mechanical properties, conformational ensembles, and relative stabilities.
Alzheimer's disease is a neurodegenerative disease caused due to aggregation of Aβ peptides i... more Alzheimer's disease is a neurodegenerative disease caused due to aggregation of Aβ peptides in the brain tissues. Recently, several studies on Alzheimer's disease transgenic mice have shown the effect of caffeine in significantly reducing the Aβ amyloid level in their brains. However, the mechanism and mode of caffeine action on amyloid aggregation are not known. Therefore, in this study, we have carried out molecular dynamics simulation of five amyloid forming Aβ16-22 peptide in pure water and in a regime of caffeine solutions, with different caffeine : peptide stoichiometric ratios. The secondary structure analyses of peptides in pure water show the formation of β-sheet conformation, whereas on addition of caffeine these ordered conformation become negligible. Radial distribution function, contact map, nonbonding interaction energy, hydrogen bonding, potential of mean force and hydration analyses show less inter-peptide interaction in presence of caffeine, and the effect i...
To examine the molecular level understanding of temperature induced self-association of caffeine ... more To examine the molecular level understanding of temperature induced self-association of caffeine molecules in aqueous solution both in the presence and absence of salt NaCl, we have performed long MD simulations at a regime of temperatures ranging from 275 to 350 K with a temperature difference of 25 K. The calculations of different site-site radial distribution functions followed by coordination number analyses, the calculations of preferential interaction parameters, solvent accessible surface area, and cluster structure analyses show a depletion in the caffeine association propensity with increasing temperature. We have also observed the salting out effect of caffeine molecules in salt solution. The simultaneous presence of polar and nonpolar groups in a caffeine molecule leads to anisotropic hydration. Specifically, the hydration tendency of caffeine hydrophobic sites increases with increasing temperature, while hydrophilic sites tend to be less hydrated. This leads to a decrease in caffeine association. In accordance with some experimental studies on thermodynamics of caffeine association, we have also observed enthalpy driven association in pure water. But the presence of salt leads to entropy driven association specifically at higher temperature. This is due to the relatively stronger interactions of salt ions with caffeine at higher temperature.
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Papers by Bhanita Sharma