Bernard Brooks

ABSTRACT Molecular modeling and energy calculations have been used to study how delta-hemolysin a... more ABSTRACT Molecular modeling and energy calculations have been used to study how delta-hemolysin and melittin helices may aggregate on membrane surfaces and insert through membranes to form channels. In these models adjacent antiparallel amphipathic helices form planar &quot;raft&quot; structures, in which one surface is hydrophobic and the other hydrophilic. Models of delta-hemolysin crystal structure were developed using these &quot;rafts.&quot; These models are based on the unit cell constants and the crystal symmetry obtained from the preliminary crystal data. Energy calculations favor channel models of delta-hemolysin with six or eight monomers per channel.

Alternate Pathways for Acetic Acid and Acetate ion Release from Acetylcholinesterase: a Molecular Dynamics Study

Journal of the American Chemical Society, 1998

Two competing passageways for the exit of acetic acid and acetate ion in Torpedo californica (Tc)... more Two competing passageways for the exit of acetic acid and acetate ion in Torpedo californica (Tc) acetylcholinesterase (ACHE) were studied by examining free energies of passage through two potential trajectories using the umbrella sampling technique as implemented in CHARMM. The coordinates for migration were defined as the distance from Ser200 Oγ, one through the 20-Å long active-site gorge ending with Trp279 and a 14-Å long route ending at Arg244. The free energies were calculated in successive windows 0.5 Å wide for 40-90 ps. The potential of mean force (PMF) was calculated along the coordinate for migration. The PMF for the migration of acetic acid decreases by ∼8 kcal/mol after 8-Å travel through the main gorge. The PMF profile for acetate ion migration falls to a 6 kcal/mol lower value than for acetic acid migration in the main gorge. The free energy barrier for the migration of acetate ion is 1.5 kcal/mol due to a constriction formed by Tyr121, Phe290, Phe330, and Phe331 in the main gorge. The interaction between acetic acid/ acetate ion and the OH group of Tyr121 appears to guide product release through the main gorge. Acetate ion remains hydrogen-bonded to Tyr121 until it approaches Trp279 when it is expelled into bulk water. Acetic acid encounters a 6 kcal/mol barrier through the alternate pathway, while the PMF for acetate ion drops ∼27 kcal/mol when it approaches Arg244. This is the lowest energy path. Full molecular dynamics simulations, free of restraint for 170 ps, result in the migration of acetate ion through the short channel but not through the main gorge. The results indicate that if the nascent acetic acid should ionize within 3.5 Å from Ser200 Oγ, it would be more likely to exit via the alternate channel than through the main gorge.

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Correcting for the free energy costs of bond or angle constraints in molecular dynamics simulations

Biochimica et biophysica acta, 2015

Free energy simulations are an important tool in the arsenal of computational biophysics, allowin... more Free energy simulations are an important tool in the arsenal of computational biophysics, allowing the calculation of thermodynamic properties of binding or enzymatic reactions. This paper introduces methods to increase the accuracy and precision of free energy calculations by calculating the free energy costs of constraints during post-processing. The primary purpose of employing constraints for these free energy methods is to increase the phase space overlap between ensembles, which is required for accuracy and convergence. The free energy costs of applying or removing constraints are calculated as additional explicit steps in the free energy cycle. The new techniques focus on hard degrees of freedom and use both gradients and Hessian estimation. Enthalpy, vibrational entropy, and Jacobian free energy terms are considered. We demonstrate the utility of this method with simple classical systems involving harmonic and anharmonic oscillators, four-atomic benchmark systems, an alchemi...

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Thermodynamics

Thermodynamics Is the study of heat and its transformation into mechanical energy. The word therm... more Thermodynamics Is the study of heat and its transformation into mechanical energy. The word thermodynamics stems from Greek word meaning "movement of heat". not only that but thermodynamics was developed in the mid 1800,before the atomic and molecular nature of matter was understand, the foundation of thermodynamics is the conservation of energy and the fact that heat flows from hot to cold and not the other way around.

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Linear Stability Conditions for a First Order 4-Dimensional Discrete Dynamic

Journal of Applied & Computational Mathematics, 2014

Linear stability conditions for a first order 4-dimensional discrete dynamic are derived in terms... more

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Models of δ-hemolysin membrane channels and crystal structures

Proteins: Structure, Function, and Genetics, 1990