Molecular dynamics simulation of the gramicidin channel in a phospholipid bilayer.

Abstract

A molecular dynamics simulation of the gramicidin A channel In an explicit dimyrsoyl posphatidylcholine bilayer was generated to study the details of lipidprotein interactions at the microscopic level. Solid-state NMR properties of the channel averaged over the 500 psec trajectory are in excellent agreement with available experimental data. In contrast with the aption of macroscopic models, the membrane/solution interface region is found to be at leat 12 A thick. The tryptophan side chains, located within the interface, are found to form hydrogen bonds with the ester carbonyl groups of the lipids and with water, suggeng thelr important contribution to the stability of membrane proteins. Individual lipid-protein interactions are seen to vary from near 0 to -50 kcal/mol. The most strongly interacting formations are short-lived and have a nearly equal contribution from both van der Waals and electrostatic energ. This approach for per. forming molecular dynamics simulations of membrane proteis in explicit phosphollpid bilayers should help In studying the structure, dynamics, and energetics of lipid-protein interactions.The scarcity of information about the structure of membrane proteins, along with the complexity of the bilayer environment, makes an understanding of lipid-protein microscopic interactions difficult. Structure prediction algorithms of membrane proteins often represent the membrane/solution interface as a sharp demarcation between a hydrophobic and a hydrophilic environment (1, 2). Such a simplified view may not be sufficient. For example, although the amino acids of membrane proteins are generally distributed according to their hydrophobicity (2), the reasons why tryptophan and other aromatic residues are often found at the membrane/solution interface are not well understood (3). Despite numerous experimental studies, little or no detailed information is available about the microscopic nature ofthe lipid bilayer/protein bulk solution interface and its implications for lipid-protein interactions. In principle, the powerful molecular dynamics approach for studying biological macromolecules (4) can be used to gain insight into the structure and dynamics of membraneprotein complexes. In practice, extension of current computational methods to simulate a protein in an explicit phospholipid bilayer represents a major challenge. The dynamical stability and the computed properties of the system will depend on two important factors: (i) the choice of a carefully constructed starting configuration (5) and (ii) the ability of the empirical potential function to represent accurately the balance between hydrophobic and hydrophilic forces. The selection of a model system is important in that a large body ofexperimental data should be available for assessing the simulation's validity. This paper describes a systematic approach for constructing the starting configuration for molecular dynamics simulations of intrinsic membrane proteins and reports on the results of a 500-psec trajectory for an 8:1 dimyristoyl ...

Initial steps of inactivation at the K + channel selectivity filter

“…Molecular dynamics simulations were performed using the MthK pore structure in high [K + ] (Protein Data Bank ID code 1LDC) (13) using methods described previously (45). Briefly, molecular systems were assembled using the CHARMM-GUI web service (46) using a protocol developed by Woolf and Roux (47). The channel protein, with its symmetry axis aligned along the z axis, was embedded in a lipid bilayer of dipalmitoyl-phosphatidylcholine molecules.…”

Molecular Dynamics Simulation of Crystal-Induced Membranolysis

“…The construction method was developed by Woolf and Roux and applied to the simulation of gramicidin and pf1. 24,25 In brief, the general strategy for creating a reasonable starting configuration for a phospholipid system consisted of randomly selecting lipids from a pre-equilibrated and pre-hydrated set and then placing them in a bilayer. The number of core-core overlaps between heavy atoms were reduced through systematic rotations (around the z-axis) and translations (in the xy plane) of the lipids.…”

Empirical force fields for biological macromolecules: Overview and issues

“…165 Optimization of the force field targeting small molecules in the gas phase was performed without atom truncation, while condensed phase tests employed atom truncation. This force field was used in a number of studies, including lipids, 270 a micelle, 271 and protein-lipid complexes, 272 reproducing a variety of experimental observables. However, application of that force field in crystal simulations of glycerolphosphorylcholine and cyclopentylphosphorylcholine yielded densities that were too high.…”