Coarse-grained modeling of allosteric regulation in protein receptors

Abstract

Allosteric regulation provides highly specific ligand recognition and signaling by transmembrane protein receptors. Unlike functions of protein molecular machines that rely on large-scale conformational transitions, signal transduction in receptors appears to be mediated by more subtle structural motions that are difficult to identify. We describe a theoretical model for allosteric regulation in receptors that addresses a fundamental riddle of signaling: What are the structural origins of the receptor agonism (specific signaling response to ligand binding)? The model suggests that different signaling pathways in bovine rhodopsin or human β 2 -adrenergic receptor can be mediated by specific structural motions in the receptors. We discuss implications for understanding the receptor agonism, particularly the recently observed "biased agonism" (selected activation of specific signaling pathways), and for developing rational structure-based drug-design strategies. allostery | signal transduction | agonism | GPCRA llostery [Greek for "other site" (1, 2)] indicates a mechanism in which a stimulus acting at a regulatory protein site (often called the orthosteric site or the effector site) causes a response at a spatially distant functional site (the allosteric site) (3). Allosteric regulatory mechanisms (i.e., regulation of protein functions by binding an effector molecule at an allosteric site) are ubiquitous throughout biology; they control vital biomolecular and cellular functions, including enzymatic catalysis and biosynthesis, molecular recognition and response to messengers, cell signaling, energy transduction, cell division and cancer, and many others (4-7). Signaling is perhaps the most fascinating and significant set of processes in which allosteric communication plays a central role (8, 9); biochemical signaling pathways lie at the core of most biological processes in cells, most notably signaling responses to binding endogenous ligands and drugs (10-12). Therefore, an understanding of allosteric signal transduction mechanisms in protein receptors is critical for describing cell regulation.The investigation of allosteric regulatory mechanisms in signaling is difficult because of the complexity of receptor structure, the presence of thermal fluctuations, the range of relevant time scales, and, often, the subtlety of the underlying structural changes (13-15). Although experimental techniques such as FRET (16), time-resolved X-ray crystallography (17), time-resolved spectroscopy (18), cryo-EM (19), and biochemical methods (20, 21) provide valuable insights into specific aspects of allosteric interactions, a comprehensive atomic-level description of the connection between receptor structure and signaling is still beyond reach. As such, advanced computational methods could be instrumental for revealing the structural origins of allosteric regulation in signal transduction.Computational approaches have been used recently in attempts to explore signal transduction in receptors. Although all-atom molecular dynamics (M...

The Membrane Complex between Transducin and Dark-State Rhodopsin Exhibits Large-Amplitude Interface Dynamics on the Sub-Microsecond Timescale: Insights from All-Atom MD Simulations

“…Finally, several rhodopsin residues that are found to interact with transducin in our all-atom MD simulation (e.g., residues 67, 150, 223, 242-247, and 323, as well as the C-terminal residues) have been recently identified as potential allosteric sites using a coarse-grained modeling approach. 50 Similar findings were obtained from a sequence-based covariance analysis that indicates a network of evolutionarily conserved connections among similar residues in rhodopsin. 51 Our results corroborate these findings and further suggest the regions in transducin that recognize these regions to convey the allosteric signal across the protein interface.…”

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

“…In accordance with FRET and the simulation data, we therefore propose that binding of ATP to FAK induces a tightly closed FERM/kinase conformation by rigidifying the interaction interfaces. Moreover, by performing an elastic network-based allosteric connectivity analysis of the FAK domain, we find, by a completely independent computational approach (38), a strong allosteric coupling between αC-and αG-helices despite their distal locations (Fig. S6).…”

Slow Protein Conformational Change, Allostery and Network Dynamics

“…In this case, signal propagation requires a network of mechanical strain relaying residues with mechanical properties distinguishing them well from the surroundings to minimize thermal dissipation -Notice that distortion of a soft donut at one side has negligible effect on another side of the donut. Mechanical stresses due to effector molecule binding irradiate from the binding site, propagate through the relaying network, and con-focus on the reaction region at the other side of the protein (Amaro et al, 2009;Amaro et al, 2007;Balabin et al, 2009;Cecchini et al, 2008;Cui and Karplus, 2008;Horovitz and Willison, 2005;Ranson et al, 2006). However, it is challenging to transmit the mechanical energy faithfully against thermal dissipation over a long distance.…”