UCSF

Allostery describes altered protein function at one site due to a perturbation at another site. One mechanism of allostery involves correlated motions, which can occur even in the absence of substantial conformational change. I present two novel information-theoretic molecular dynamics simulation analysis methods, one based on the mutual information and another based on the Kullback-Leibler divergence, to identify statistically significant correlated motions from equilibrium molecular dynamics simulations and statistically significant torsional population shifts when comparing sets of simulations under different conditions. I describe applications of these methods, and then novel experiments and kinetic modeling regarding the enzymology of caspase-1. These showed caspase-1's robust cooperativity requires substrate or inhibitor-assisted dimerization, and that even within the dimer, the enzyme is more active when two substrates are bound than when one substrate is bound.