Hydrogenases are enzymes that catalyze the reversible conversion of hydrogen molecules (H2) to protons and electrons in a very efficient manner.
Due to their high catalytic activity, they have attracted interest as potential catalysts for biofuel cells. However, one major problem that hampers application of hydrogenases on an industrial scale is their inhibition by oxygen molecules present in the atmosphere. The oxygen sensitivity of these enzymes make them interesting objects for computational compound design:
the enzyme may
be mutated so as to block access of O2 and other inhibitor gases (CO) to the active site, while leaving diffusion/migration of H2 unaffected.
Here we present a novel multiscale molecular dynamics approach for the simulation of gas diffusion in proteins and apply our new method to [NiFe]-hydrogenase.
the chemical compound space of diatomic gas molecules, we find that H2 and
similar diffusion paths that are distinct from the one of CO. While H2 and
reach the active site via a diverse network of accessible pathways, CO diffusion is limited to a well-defined hydrophobic gas channel. Altering the composition of the protein residues lining up this channel, we find that CO diffusion into the active site can be dramatically reduced without affecting H2 diffusion, in agreement with experimental measurements. We argue that a similar `gas filter'
could be engineered for O2 by modifying a specific protein residue in the active site pocket. Our contribution shows how novel molecular simulation techniques can provide the atomistic picture that is needed for a rational design of proteins with desired properties.