Graphs of Hydrogen-Bond Networks to Dissect Protein Conformational Dynamics

Abstract

Dynamic hydrogen bonds and hydrogen-bond networks are ubiquitous in proteins and protein complexes. Functional roles that have been assigned to hydrogen-bond networks include structural plasticity for protein function, allosteric conformational coupling, long-distance proton transfers, and transient storage of protons. Advances in structural biology provide invaluable insights into architectures of large proteins and protein complexes of direct interest to human physiology and disease, including G Protein Coupled Receptors (GPCRs) and the SARS-Covid-19 spike protein S, and give rise to the challenge of how to identify those interactions that are more likely to govern protein dynamics. This Perspective discusses applications of graph-based algorithms to dissect dynamical hydrogen-bond networks of protein complexes, with illustrations for GPCRs and spike protein S. H-bond graphs provide an overview of sites in GPCR structures where hydrogen-bond dynamics would be required to assemble longer-distance networks between functionally important motifs. In the case of spike protein S, graphs identify regions of the protein where hydrogen bonds rearrange during the reaction cycle and where local hydrogen-bond networks likely change in a virus variant of concern.

Fentanyl and the Fluorinated Fentanyl Derivative NFEPP Elicit Distinct Hydrogen-Bond Dynamics of the Opioid Receptor

“…Recent developments in structural biology, which enabled a detailed molecular picture of how morphine, fentanyl, and other related compounds interact with human MOR, provide the foundation for future experimental and computational studies to evaluate proton-coupled drug binding. Given the significant impact that resolution of the structure and the internal water molecules have on the internal H-bond networks of membrane proteins, including GPCRs, ,, higher-resolution structures of apo- and ligand-bound human MOR with internal water molecules will be needed to characterize proton sensitivity of the human receptor.…”

Dynamics of Hydrogen Bonds between Water and Intrinsically Disordered and Structured Regions of Proteins

“…Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of otherwise structured proteins are ubiquitous and involved in many signaling and regulatory processes. − Interactions between proteins and water and the dynamics of water around proteins play key roles in protein function, including enzyme activity and allostery, , and while these properties have been extensively studied for structured proteins, − less is known for IDPs and proteins with IDRs. Some studies indicate more restricted dynamics of water around IDRs and IDPs compared to structured systems of similar size, − the origin of which appears to be due at least in large part to a greater presence of charged groups in disordered regions .…”

Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68

“…Dynamic protein-water H-bond networks are thought essential for propagation of agonist-induced conformational changes leading to the formation of an active receptor state [43] , [49] , [50] , [92] . The internal protein-water H-bond network of a pH-sensing GPCR such as GPR68 would thus need to respond to changes in the protonation state.…”

“…Graph computations of dynamic H-bond networks . Dynamic H-Bond Networks and water wires were calculated using Bridge2 [90] , [91] , [92] . Briefly, Bridge2 is a set of graph-based algorithms with graphical user interface for highly efficient computations of protein-water H-bond networks.…”