The relationship between local frustration and protein function

Energy landscape theory is the accepted theoretical framework for understanding protein folding based on minimizing frustration. The theory provides an algorithm to learn the energy of amino acid interactions within a folded protein structure that also allows evaluation of localized regions of frustration. Most amino acid contacts are minimally frustrated or neutral, but patches of amino acid contacts are highly frustrated. These energetically unfavorable interactions are mostly found on the protein surface and have been linked to protein function in various ways. This review highlights experimental and computational exploration of how localized energetic frustration is linked to protein function.