Protein Sequence Design by Conformational Landscape Optimization
Protein sequence design by conformational landscape optimization Christoffer Norna,b,1, Basile I. M. Wickya,b,1, David Juergensa,b,c, Sirui Liud, David Kima,b, Doug Tischera,b, Brian Koepnicka,b, Ivan Anishchenkoa,b, Foldit Players2, David Bakera,b,e,3, and Sergey Ovchinnikovd,f,3 aDepartment of Biochemistry, University of Washington, Seattle, WA 98105; bInstitute for Protein Design, University of Washington, Seattle, WA 98105; cGraduate Program in Molecular Engineering, University of Washington, Seattle, WA 98105; dFaculty of Arts and Sciences, Division of Science, Harvard University, Cambridge, MA 02138; eHoward Hughes Medical Institute, University of Washington, Seattle, WA 98105; and fJohn Harvard Distinguished Science Fellowship Program, Harvard University, Cambridge, MA 02138 Edited by Barry Honig, Columbia University, New York, NY, and approved January 27, 2021 (received for review August 14, 2020) The protein design problem is to identify an amino acid sequence scale stochastic folding calculations, searching over possible that folds to a desired structure. Given Anfinsen’s thermodynamic structures with the sequence held fixed (9). This two-step pro- hypothesis of folding, this can be recast as finding an amino acid cedure has the disadvantage that the structure prediction cal- sequence for which the desired structure is the lowest energy culations are very slow, requiring many central processing unit state. As this calculation involves not only all possible amino acid (CPU) days for adequate sampling of protein conformational sequences but also, all possible structures, most current ap- space. Moreover, there is no immediate recipe for updating the proaches focus instead on the more tractable problem of finding designed sequence based on the prediction results—instead, the lowest-energy amino acid sequence for the desired structure, sequences that do not have the designed structure as their often checking by protein structure prediction in a second step lowest-energy state are typically discarded.
[Show full text]