11/13/2022 0 Comments Membrane structures calculation![]() ![]() ![]() ![]() (19) To date, most studies (5,11,18,20,21) have combined umbrella sampling with a potential of mean force (PMF) calculation along a one-dimensional reaction coordinate connecting the binding site with the surrounding membrane (18) ( Figure 1B). Membrane proteins and lipids pose particular challenges of sampling and convergence for accurate free energy estimation, (18) arising from the relatively slow rates of lipid diffusion and from the diversity of lipid species present in complex biological membranes. Several free energy techniques have been developed for the calculation of binding free energies between ligands and (water soluble) proteins, (17) and these can be modified for analysis of protein–lipid interactions. Molecular simulations can also be used to quantify the strength of protein–lipid interactions, via free energy calculations ( Figure 1A). We demonstrate good agreement between the different techniques, providing a robust framework for their automated implementation within a pipeline for annotation of newly determined membrane protein structures. We employ these techniques within the framework of a coarse-grained force field and apply them to both bacterial and mammalian membrane protein–lipid systems. We demonstrate that the energetics of protein–lipid interactions may be reliably and reproducibly calculated using three simulation-based approaches: potential of mean force calculations, alchemical free energy perturbation, and well-tempered metadynamics. Molecular dynamics simulations provide the primary computational technique to estimate the free energies of these interactions. The structures of protein–lipid complexes can be determined through a combination of experimental and computational approaches, but the energetic basis of these interactions is difficult to resolve. Integral membrane proteins are regulated by specific interactions with lipids from the surrounding bilayer. ![]()
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