Molecular Dynamics Simulations of Membrane Proteins: Getting the Details Right

Abstract

Over the past decade atomistic molecular dynamics simulations have become an established tool for studying the conformational dynamics and interactions with local environment of membrane proteins. While a great deal of valuable, molecular-level insight has been obtained from such simulations, in order to fully utilise their predictive power, it is important to continually validate and improve the methods and models that are used.The accuracy of molecular dynamics simulations is dependent upon the quality of the force fields used to describe the interactions between particles in the system. Whilst numerous studies have compared different atomistic protein force fields, there have been fewer studies comparing force fields for membranes/membrane protein simulations. Thus it is timely to initiate such a study.In the present work, we have tested the accuracy of five atomistic force fields used to simulate two different phospholipid membranes (namely the zwitterionic DPPC and POPC lipids). Multiple simulations, each 200 ns in length, have been performed to evaluate the reproduction of a range of physical properties. In addition, we have performed simulations of six different membrane proteins (3 alpha-helical and 3 beta-barrel proteins of varying size: melittin, KcsA, mitochondrial ADP/ATP carrier, OmpA, OmpG and FhuA) in both DPPC and POPC membranes using the same five lipid force fields, combined with appropriate protein force fields. Our simulations, which are in total over 60 microseconds in length, allow for a systematic comparison between frequently used combinations of lipid and protein force fields and thus will be a valuable resource for the membrane protein simulation community.