Research

We study the atomic details of enzymatic catalysis.
The microscopic mechanism of enzyme catalysis remains a hotly debated topic.
We have proposed that in certain enzymes, motions in the body of the protein
are an integral part of the chemical mechanism.
This was controversial because these motions are much faster than the
turnover rate, but work by us and other groups have verified this effect.
There are 2 practical difficulties in computer simulations of enzymes:
the accessible simulation times are much shorter than biologically important timescales,
and the enzymatic reaction coordinate is unknown.
We develop and employ rare event simulation tools such as Transition Path Sampling to
overcome these obstaclesand provide unbiased mechanistic information.
We also work on incorporating these insights into methodologies of enzyme design
and studies of enzyme evolution.

We perform computational studies of point mutations in cardiac thin filament.Calcium binding and dissociation within the cardiac thin filament is a fundamentalregulator of normal contraction and relaxation.Mutations that disrupt this allosterically mediated process have long been implicated incardiomyopathy, but atomic details of the mechanism remain elusive, preventing thedesign of new targeted therapies.We built the first computer model of the thin filament of cardiac muscle and oursimulations pinpointed how mutations in one protein of a complex indirectly affect asecond protein via structural and dynamic changes in a third protein,resulting in a pathogenic change in thin filament function.This atom-level insight is potentially highly actionable in drug design.