Symmetric Ligand Binding Pathways and Dual-State Bottleneck in [NiFe] Hydrogenases from Unbiased Molecular Dynamics

02 June 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

[NiFe] hydrogenases are a family of enzymes that can be used to produce biofuel, thus making them important for industrial applications. In this work, we utilized unbiased molecular dynamics (UMD) simulations to capture binding and unbinding events of the substrate, H2, to and from the [NiFe] hydrogenases from two different organisms. We obtained multiple (un)binding events and reproduced experimental association rate constants. We observed symmetry between the binding and unbinding pathways used by H2 to access or leave the catalytic site. Moreover, we found that the main bottleneck for ligand binding, the distance between residues V74 and L122, can shift between two states with different bottleneck widths, a feature which can be exploited to modulate the access of small molecules to the catalytic site. The pathway probabilities presented here can be used to benchmark enhanced sampling methods which investigate protein-ligand binding.

Keywords

[NiFe] Hydrogenase
Molecular Dynamics Simulation
Binding Kinetics

Supplementary materials

Title
Description
Actions
Title
H2ase-UMD-Binding-SI
Description
Supporting Information of the "Symmetric Ligand Binding Pathways and Dual-State Bottleneck in [NiFe] Hydrogenases from Unbiased Molecular Dynamics" paper.
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