TY - JOUR T1 - Protein Design Using Continuous Rotamers A1 - Gainza, Pablo A1 - Roberts, Kyle E. A1 - Donald, Bruce R. Y1 - 2012/01/12 N2 - Author Summary Computational protein design is a promising field with many biomedical applications, such as drug design, or the redesign of new enzymes to perform nonnatural chemical reactions. An essential feature of any protein design algorithm is the ability to accurately model the flexibility that occurs in real proteins. In enzyme design, for example, an algorithm must predict how the designed protein will change during binding and catalysis. In this work we present a large-scale study of 69 protein redesigns that shows the necessity of modeling more realistic protein flexibility. Specifically, we model the continuous space around low-energy conformations of amino acid side chains, and compare it against the standard rigid approach of modeling only a small discrete set of low-energy conformations. We show that by allowing the side chains to move in the continuous space around low energy conformations during the protein design search, we obtain very different sequences that better match real protein sequences. Moreover, we propose a new protein design algorithm that, contrary to conventional wisdom, shows that we can search the continuous space around side chains with close to the same efficiency as algorithms that model only a discrete set of conformations. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 8 IS - 1 UR - https://doi.org/10.1371/journal.pcbi.1002335 SP - e1002335 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002335 ER -