Computer Simulations of Membranes and Biopolymers

National Heart, Lung, And Blood Institute

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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 Progress was made three fronts: (i) developing a model for PIP2/PLD2 rafts; (ii) determining the structure of the newly discovered induced ordered domain (IOD), which is found in the leaflet opposing a liquid ordered phase in asymmetric membranes; (iii) showing the disruption of an IOD by xenon (a general anesthetic). Aim 2. Develop Simulation Methodology As reported in ref 1, results for the Drude polarizable force field (noted in the 2024 Annual Report) was compared with those of the additive FF, C36. The increase in viscosity associated with polarizability reduced the translation diffusion coefficients of DPPC and DOPC yielding agreement with experiment, providing a critical validation of the new FF. It was also shown that pore formation in membranes by influenza fusion peptide is enhanced by polarizability, demonstrating the importance of including polarizability in simulations of membrane remodeling. Refs 2 and 3 appeared as chapters in Methods of Enzymology, and described the use of Binary Bilayer Systems and P21 boundary conditions for simulations of complex bilayers, respectively. Ref 4 is the 15 year update on CHARMM (Chemistry at HARvard Macromolecular Mechanics), the simulation program used worldwide. Aim 3. Simulate Complex Membranes Simulations this year focused on the antimicrobial peptide piscidin 1 (P1). Ref 5 describes simulations of P1 on asymmetric membranes in the area stressed (AS) and area relaxed (AR) states. The AS showed defect rates 10 time higher than the AR. These results promoted the evaluation of the free energy of pore formation reported in Ref 6. Pore from AS initial conditions are substantially more stable than those from AS, and the AS revert to the AR as lipids and peptide translocate. This, and further analysis, yield a model of AMP action that explains both graded and all-or-none leakage. These insight are currently being applied to understand the mechanism of cell penetrating peptides.