This project focuses on the study of membranes, proteins and carbohydrates by molecular dynamics computer simulation. Progress is reported under each Aim listed above Aim 1. Understand Model Membranes.
This Aim concerned a simulation-based test of a near-universal assumption made in the experimental determination of spontaneous curvatures of lipids: that the spontaneous curvature of a lipid mixture can be obtained by simply adding the spontaneous curvature of each component in the pure state. Our simulations indicated that this assumption is not correct in some very important cases, including bilayers containing sphingomyelin (which can hydrogen bond to each other as concentration increases) and DPPC/cholesterol (where condensation changes the spontaneous curvature). The implication of this observation is critical for understanding rafts in cell membranes, because a shift in the lipid composition can change the sign of the spontaneous curvature. The simulations indicate that the liquid disordered phase of DPPC/DOPC/cholesterol has negative curvature (consistent with the additive assumption) while liquid ordered phase has positive curvature (inconsistent with the additive assumption). The study, Nonadditive compositional curvature energetics of lipid bilayers by Alexander J. Sodt, Richard M. Venable, Edward Lyman, and Richard W. Pastor, is presently in press in Physical Review Letters.
Aim 2. Develop Simulation Methodology.
The Aim also yielded a ground breaking result: a theoretical prediction that periodic boundary conditions used in virtually all simulations of membranes lead to large artifacts in the diffusion constants of lipids and proteins (Strong influence of periodic boundary conditions on lateral diffusion in lipid bilayer membranes. Brian A. Camley, Michael G. Lerner, Richard W. Pastor, and Frank L.H. Brown, Journal of Chemical Physics, 143, 243113-243124, 2015). We then used simulations at different size simulation cells to validate the theory, and developed a Bayesian-based method to extrapolate simulated diffusion constants to infinite system size and thereby compare with experiment. (Lipid and peptide diffusion in bilayers: the Saffman-Delbrck model and periodic boundary conditions. Richard M. Venable, Helgi I. Inglfsson, Michael G. Lerner, B. Scott Perrin, Jr., Brian A. Camley, Siewert J. Marrink, Frank L.H. Brown, and Richard W. Pastor. J. Phys. Chem. B, submitted for publication).
Aim 3. Simulate Complex Membranes Multimicrosecond simulations requiring two years of allocations on the Anton supercomputer showed that the CHARMM36 force field developed in our group successfully yields that stable pore experimentally observed for the peptide alamethicin (Simulations of membrane disrupting peptides I: Alamethicin pore stability and spontaneous insertion. B. Scott Perrin Jr. and Richard W. Pastor. Biophysical Journal, in press.) In contrast, similar pores of the antimicrobial peptide (AMP) piscidin 1 were not stable, and the individual peptide diffusion to the membrane surface during the simulations. Hence, these results disprove the toroidal pore hypothesis for the mechanism of disruption of piscidin 1, and likely other AMPs (Simulations of membrane disrupting peptides II: AMP Piscidin 1 favors surface defects over pores. B. Scott Perrin Jr, Riqiang Fu, Myriam L. Cotten, M. and Richard W. Pastor, Biophysical Journal, in press). The determination of the disruption mechanism of AMPs is the present goal of our work.
Showing the most recent 10 out of 52 publications
