On the functional significance of soft modes predicted by coarse-grained models for membrane proteins

Recent years have seen an explosion in the number of studies that explore the collective dynamics of biomo-lecular systems using coarse-grained (CG) models along with methods based on principal component analysis (PCA). Among them, elastic network models (ENMs) and normal mode analyses (NMAs) have found wide use in several applications. Recent studies are now providing evidence for the usefulness of these methods in exploring the dynamics of membrane proteins. The type of motions explored by the ENMs represents a different regime compared with the highly specific chemical events and electrostatic interactions that are usually explored by molecular dynamics (MD) simulations. These are collective motions that cooperatively involve all subunits, usually exploit the symmetry of the quater-nary structure, and facilitate mechanical functions such as pore opening and allosteric communication. Understanding the mechanisms of function of membrane proteins using computational methods may necessitate adopting multi-scale approaches that integrate ENM-based methods with full atomic simulations. Modeling and simulating the dynamics of membrane proteins is usually a challenge due to the complexity of their interactions with ions, ligands, lipids, and water molecules, and the interplay of chemical and mechanical events at multiple scales that may be controlling their function. The potential of CG models and methods, such as ENM-based NMA, to convey physically and biologically meaningful results concerning membrane protein dynamics and function may therefore be open to discussion, even though such studies prove useful in other applications, e.g., in understanding the role of the intrinsic dynamics of proteins in substrate recogni-ing events at the molecular level (Bahar et al., 2007; Chennubhotla et al., 2008). Here, we present a brief overview of the foundations and basic assumptions of these CG approaches, the motivation and justification behind their use, apart from their simplicity, and what we have learned from the ENM analyses of membrane proteins in recent years (Bahar et al., 2010a). These studies suggest that, despite the complexity and specificity of their interactions, membrane proteins possess , like other proteins, intrinsic dynamic features that are purely defined by their three-dimensional fold/ shape; and like other proteins, they exploit their particular structure-encoded dynamics for achieving key mechanical functions such as gating, pore opening, or allosteric signaling; and ENM-NMA is a uniquely versatile approach for assessing such collective mechanical events and appears as a promising tool to be used in conjunction with other (higher resolution) approaches for elucidating membrane protein dynamics. We also point to the …