Computational approaches to detect allosteric pathways in transmembrane molecular machines

Abstract

Many of the functions of transmembrane proteins involved in signal processing and transduction across the cell membrane are determined by allosteric couplings that propagate the functional effects well beyond the original site of activation. Data gathered from breakthroughs in biochemistry, crystallography, and single molecule fluorescence have established a rich basis of information for the study of molecular mechanisms in the allosteric couplings of such transmembrane proteins. The mechanistic details of these couplings, many of which have therapeutic implications, however, have only become accessible in synergy with molecular modeling and simulations. Here, we review some recent computational approaches that analyze allosteric coupling networks (ACNs) in transmembrane proteins, and in particular the recently developed Protein Interaction Analyzer (PIA) designed to study ACNs in the structural ensembles sampled by molecular dynamics simulations. The power of these computational approaches in interrogating the functional mechanisms of transmembrane proteins is illustrated with selected examples of recent experimental and computational studies pursued synergistically in the investigation of secondary active transporters and GPCRs.

MHC class II complexes sample intermediate states along the peptide exchange pathway

“…Pairwise interactions and their significant differences between pairs of metastable states were detected with a modification of the system-wide Pairwise Interaction Analyser7576: For every simulation frame assigned to a metastable conformation, a pairwise interaction between two sets of heavy atoms (for example, the heavy side-chain or backbone atoms a residue) is inferred to exist, if the two sets fulfill certain geometric criteria evaluated by the program HBPLUS77, or the program VMD78 (using a distance criterion provided in ref. 79).…”

How Do Short Chain Nonionic Detergents Destabilize G-Protein-Coupled Receptors?

“…28-31 However, MD simulations have not been used to study the stability of GPCRs embedded in detergent micelles. The receptor we have used for this study, the human adenosine A 2A receptor (A 2A R), was chosen because its stability in lipid bilayers has already been thoroughly studied by MD simulations, both for the wild type receptor and engineered thermostable mutant in different conformations.…”

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations

“…Extracting relevant allosteric pathways from simulations of proteins is a longstanding problem and a number of approaches have been developed (see e.g. [43–45] for reviews of these methods). Such methods have been applied to study various GPCRs, including the A 2A -adenosine receptor [46], β 2 AR [18], dopamine receptors [47], luteinizing hormone receptor [48], MOR [7], rhodopsin [49, 50], and 5HT 2A serotonin receptor [51, 52].…”