Role of the biomolecular energy gap in protein design, structure, and evolution.

The folding of natural biopolymers into unique three-dimensional structures that determine their function is remarkable considering the vast number of alternative states and requires a large gap in the energy of the functional state compared to the many alternatives. This Perspective explores the implications of this energy gap for computing the structures of naturally occurring biopolymers, designing proteins with new structures and functions, and optimally integrating experiment and computation in these endeavors. Possible parallels between the generation of functional molecules in computational design and natural evolution are highlighted.