Abstract

Due to polymorphism and the long timescales involved, it is difficult to characterise the precise nature of protein-ligand interactions experimentally. Many biological systems exhibit broken ergodicity, thus limiting the usefulness of standard molecular dynamics and Monte Carlo procedures. Basin-hopping and discrete path sampling provide alternative techniques that can effectively explore configuration space and provide data to construct kinetic transition networks, respectively. These methods have been applied to the enzyme HemS, which experiment suggests can regulate haem and NADH interactions to control a novel oxygen-independent haem-breakdown process. Specifically, the results presented provide new insight into the conformation of a double-phenylalanine gate – thought to be essential to the regulatory nature of the protein – and its response to the approach of NADH towards haem.