Simulating Transmembrane Proteins with the Coarse-Grained SIRAH Force Field: Tips and Tricks for Setting Up and Running in AMBER

Abstract

Biological membranes constitute enormously complex objects formed of hundreds to thousands of different species of lipids in a crowded mix with a similarly massive variety of proteins, continuously exchanging information among themselves (Harayama and Riezman, 2018). Such interactions are crucial to regulate protein function and sorting into different subcellular organelles (Chattopadhyay, 2017). Indeed, our vision of biological membranes has evolved from a passive role in the fluid mosaic model (Singer and Nicolson, 1972) to a highly complex and tightly regulated hub of interactions and signaling processes (Goñi, 2014).In parallel, advances in molecular dynamics (MD) simulations nowadays provide a perspective on the structure and dynamics of membrane systems that is difficult to achieve using experimental techniques. State-of-the-art MD can actually breach resolution gaps linking the nanoscales with the mesoscales and achieve an astonishing complexity level (Chavent et al., 2016; Marrink et al., 2019; and Pezeshkian and Marrink, 2021).Nevertheless, the elevated cost of fully atomistic descriptions has prompted the development of coarse-grained (CG) representations that reduce the computational burden while keeping an acceptable resolution in the intermolecular interactions that determine the behavior of the system. Many CG models have been reported in the literature (Ingólfsson et al., 2014). Among them, CG models that retain molecular details at a single residue level are particularly interesting since they can matchthe resolution achievable by experimental techniques, providing valuable and verifiable insights on biologically relevant systems.This chapter illustrates how to perform MD simulations of membrane proteins using the SIRAH force field for CG and multiscale simulations using the AMBER package (https://ambermd.org). SIRAH (Southamerican Initiative for a Rapid and Accurate Hamiltonian, https://www.sirahff.com) constitutes one of the most complete CG force fields reported in the literature, with topologies and parameters for most biological molecules.