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Limits of performance for protein side chain packers Brizuela, Carlos


To date, it is possible to design proteins with an improved function starting from known scaffolds. This design applies to the enhancement of enzymatic capabilities, inhibitors of protein-protein interactions, among others [1]. The next generation for the design of functional proteins will be guided by the approach known as template-free design. The goal of this approach is to design a sequence of amino acids that will have a predefined function. A more conservative approach seeks to find a chain of amino acids that will fold into a predefined backbone geometry. A central challenge to the latter approach is the side chain packing problem (SCPP) that aims to find a set of rotamers that minimizes a given scoring function, for a fixed backbone geometry associated to a candidate sequence. In this talk, we will define the computational model for the SCPP, analyze the results achieved by state-of-the-art packers, and determine a lower bound for the maximum achievable accuracy of a simple rotamer library [2]. We also show that a strong limitation to reduce the gap between state-of-the-art results and the maximum attainable accuracy is the scoring function. Furthermore, we show that the limitation in the scoring function is not related to an incorrect weighting of its components nor to the constrained geometry of the crystal [3].
[1]. P.S. Huang, S.E. Boyken, and D. Baker. ¨The coming of age of de novo protein design¨. Nature 537 (7620): 320 â 327, 2016.
[2]. J. Colbes, R.I. Corona, C. Lezcano, D. Rodriguez, C.A. Brizuela. â Protein aide-chain packing problem: is there still room for improvement.â Briefings in Bioinformatics, doi:10.1093/bib/bbw079, 2016.
[3]. J. Colbes, S. Aguila, C.A. Brizuela. â Scoring of side-chain packings: An analysis of weight factors and molecular dynamics structuresâ . Journal of Chemical Information and Modeling, 58 (2), 443-452, 2018.

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