Interrogating Low Barrier Hydrogen Bonds with Neutrons, X-rays, and Computation

TL;DR

This paper explores how the environment around hydrogen bonds affects proton delocalization in proteins using neutron diffraction, X-rays, and simulations.

Contribution

The study introduces a paired protein model and QM/MM simulations to demonstrate how distant residues influence low barrier hydrogen bonds.

Findings

Neutron diffraction and X-ray analysis reveal distinct hydrogen bond types in homologous proteins.

QM/MM simulations show distant residues can impact proton delocalization in low barrier hydrogen bonds.

Combining simulations and structural analysis could enable engineering of desired hydrogen bond properties.

Abstract

Low barrier hydrogen bonds (LBHBs) are H-bonds where the barrier to proton transfer from the donor to the acceptor atom is comparable to the quantum mechanical zero-point energy of the interaction, resulting in proton delocalization. Facile proton transfer makes LBHBs effective mechanisms for facilitating acid-base catalysis in certain enzymes, creating favored pathways of allosteric communication between distant sites during catalysis, and imparting a high degree of selectivity in binding certain substrates. How the microenvironment of H-bonded residues affects the degree of proton delocalization in a candidate LBHB is not fully understood. We use two homologous proteins, human DJ-1 and E. coli YajL, as a paired model system to investigate microenvironmental effects on LBHB formation. Neutron diffraction demonstrates that YajL has an Asp- Glu LBHB while the analogous residues in DJ-1 form a conventional H-bond, validating bond length analysis of atomic resolution X-ray crystal structures. We explored the influence of the microenvironment on LBHB character by using large quantum mechanics-molecular mechanics (QM/MM) simulations where the QM region spanned several residues. These simulations support the neutron and X-ray crystallography results, demonstrating that surprisingly distant H-bonding residues can influence the degree of proton delocalization in candidate LBHBs. With the greater accessibility of QM/MM methods, combining simulation and structurally guided sequence analysis may permit the engineering of H-bonds with desired degrees of proton delocalization.