Computer Simulations of Membranes and Biopolymers

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

This overall 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 year featured calculations of viscosity in pure bilayers (Fitzgerald et al) and peptide partitioning between the liquid ordered (Lo) and liquid disordered (Ld) phases of membranes (Park et al). In the first it was shown how the increased viscosity arising from adding polarizability greatly improves agreement of simulated and experimental lipid diffusion constants compared to those obtained with additive force fields. The second shows that single-pass membrane-spanning peptides preferentially partition into regions of the Lo phases rich in cholesterol and unsaturated lipids. Hence, varying the composition of the Lo phase allows tuning of the peptide partition coefficient. Aim 2. Develop Simulation Methodology A revision of the CHARMM Drude polarizable force field (called Drude2023) was published (Yu et al). The addition of polarizability significantly improves agreement of simulation and experiment for water permeability, and thereby yields a more realistic description of processes where polar molecules enter or translocate membranes. As noted in the summary of Aim 1, polarization also improves the description of lipid diffusion. Aim 3. Simulate Complex Membranes A combined experimental, simulation and theoretical study of how influenza fusion peptides aggregate and form pores in liposomes (Rice et al., Nature Comm.) was followed with a simulation-only study (Rice et al., Biophysical J) using lysolipids to accelerate pore formation and thereby allowing a detailed description of the process. These two papers set the stage for studies of mutated viral fusion peptides, and well as a deeper understanding of pore formation by other peptides. Simulations helped unravel the effects of stapling of peptides related to D6PV, an ApoC2 mimetic that interacts with VLDL and reduces triglycerides (Sviridov et al). The most active of the stapled peptide was showed the most interaction with the triglyceride core of the model VLDL used for the simulation. Lastly, I was the principal editor of a Special Issue the Biophysical Journal for NIH collaborator and friend Klaus Gawrisch (editorial by Soubias et al.)