Ancestral Reconstruction and the Evolution of Protein Energy Landscapes

A protein's sequence determines its conformational energy landscape. This, in turn, determines the protein's function. Understanding the evolution of new protein functions therefore requires understanding how mutations alter the protein energy landscape. Ancestral sequence reconstruction (ASR) has proven a valuable tool for tackling this problem. In ASR, one phylogenetically infers the sequences of ancient proteins, allowing characterization of their properties. When coupled to biophysical, biochemical, and functional characterization, ASR can reveal how historical mutations altered the energy landscape of ancient proteins, allowing the evolution of enzyme activity, altered conformations, binding specificity, oligomerization, and many other protein features. In this article, we review how ASR studies have been used to dissect the evolution of energy landscapes. We also discuss ASR studies that reveal how energy landscapes have shaped protein evolution. Finally, we propose that thinking about evolution from the perspective of an energy landscape can improve how we approach and interpret ASR studies.