Protein dynamics revealed by hydrogen/deuterium exchange mass spectrometry: Correlation between experiments and simulation

Abstract

Hydrogen deuterium exchange mass spectrometry (HDX‐MS) is a powerful technique for studying protein dynamics, which is an important factor governing protein functions. However, the process of hydrogen/deuterium exchange (HDX) of proteins is highly complex and the underlying mechanism has not yet been fully elucidated. Meanwhile, molecular dynamics (MD) simulation is a computational technique that can be used to elucidate HDX behaviour on proteins and facilitate interpretation of HDX‐MS data. This article aims to summarize the current understandings on the mechanism of HDX and its correlation with MD simulation, to discuss the recent developments in the techniques of HDX‐MS and MD simulation and to extend the perspectives of these two techniques in protein dynamics study.

Interdomain flexibility and interfacial integrity of β-lactamase inhibitory protein (BLIP) modulate its binding to class A β-lactamases

“…However, little work has been done on the role of flexibility or conformational dynamics of BLIP upon binding β-lactamases. Following our previous study on β-lactamases regarding their binding with BLIP ( 13 ), in this study, we focused on the conformational dynamics of BLIP and its mutants upon binding class A β-lactamases using hydrogen deuterium exchange mass spectrometry (HDX-MS) complemented with molecular dynamics (MD) simulation ( 14 ). HDX-MS can inform the hydrogen bonding and solvent accessibility of backbone amides by monitoring the exchange between the amide hydrogen and the solvent deuterium.…”

Divining Deamidation and Isomerization in Therapeutic Proteins: Effect of Neighboring Residue

“…Deprotonation of the amide nitrogen has been experimentally characterized to proceed via a base-catalyzed reaction that is quite spontaneous even at acidic conditions. [31,[39][40][41] Several studies have investigated the dependence of backbone amide acidity on the conformation and chemical environment using QM/QMMM calculations. [29,30,[35][36][37] In one of the pioneering works, Radkiewicz et al [26,27] used N-formyl-glycinamide as a model compound representing a peptide bond to calculate the relative proton affinity as a function of the ϕ and ψ dihedral angles (using HF/6-31+G*//HF/3-21G).…”

Enzyme Dynamics: Looking Beyond a Single Structure

“…Hydrogen‐deuterium exchange (HDX) is a principle that allows the identification of solvent‐exposed labile 1 H atoms that are not involved in hydrogen bonding. The basic principle involves exposing an unlabeled protein to a deuterated aqueous solvent, as time incubation allows exchange between labile 1 H in the protein and deuterons from the solvent . This allows for identification of transiently solvent‐exposed 1 H atoms since deeply buried 1 H will either not exchange or exchange on a much slower time‐scale than exposed 1 H atoms.…”