Evolution of energy landscapes in designer enzymes.

Abstract

Bottom-up design of biocatalysts provides a unique opportunity to study how the dynamic motions of enzymes change as catalytic efficiency evolves. Using detailed biophysical and molecular dynamics simulations of enzymes designed to promote a simple proton transfer reaction, we have shown that a chemical reaction can be speeded up by modulating protein conformation landscapes to cooperatively preorganize catalytic residues to enhance transition-state stabilization while minimizing competing, unproductive conformations. Moreover, the general tightening of correlated dynamical networks that include the transition state and large parts of the protein was found to induce an activation heat capacity, leading to a non-linear temperature‑activity dependence. These findings suggest that explicit consideration of both static and dynamic computational approaches could aid the design of many de novo enzymes.