A Pareto-Optimal Refinement Method for Protein Design Scaffolds

Lucas Gregorio Nivón,Rocco Moretti,David Baker,Yang Zhang

doi:10.1371/journal.pone.0059004

Lucas Gregorio Nivón, Rocco Moretti + Show 2 more

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https://doi.org/10.1371/journal.pone.0059004

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Abstract

Computational design of protein function involves a search for amino acids with the lowest energy subject to a set of constraints specifying function. In many cases a set of natural protein backbone structures, or “scaffolds”, are searched to find regions where functional sites (an enzyme active site, ligand binding pocket, protein – protein interaction region, etc.) can be placed, and the identities of the surrounding amino acids are optimized to satisfy functional constraints. Input native protein structures almost invariably have regions that score very poorly with the design force field, and any design based on these unmodified structures may result in mutations away from the native sequence solely as a result of the energetic strain. Because the input structure is already a stable protein, it is desirable to keep the total number of mutations to a minimum and to avoid mutations resulting from poorly-scoring input structures. Here we describe a protocol using cycles of minimization with combined backbone/sidechain restraints that is Pareto-optimal with respect to RMSD to the native structure and energetic strain reduction. The protocol should be broadly useful in the preparation of scaffold libraries for functional site design.

Highlights

There has been recent progress in the computational design of functional proteins and in the prediction of biomolecular interactions across a wide range of problems: ligand-protein [1] and protein-protein docking [2]; protein engineering for enzyme activity [3,4,5]; protein engineering for protein-protein interaction specificity control [6]; and the design of entirely novel protein folds with artificial sequences [7,8]
In most cases of computational design for novel function one begins with the structure of an existing protein backbone ‘‘scaffold’’ and proceeds to remodel a local pocket or interface, or to carry out more extensive backbone or loop re-configurations, in order to meet a set of functional constraints
Most crystal structures will have regions of high energy as evaluated in Rosetta or other design programs, which will lead to sequence changes in design if they are not addressed

Summary

Introduction

There has been recent progress in the computational design of functional proteins and in the prediction of biomolecular interactions across a wide range of problems: ligand-protein [1] and protein-protein docking [2]; protein engineering for enzyme activity [3,4,5]; protein engineering for protein-protein interaction specificity control [6]; and the design of entirely novel protein folds with artificial sequences [7,8]. Most crystal structures will have regions of high energy as evaluated in Rosetta or other design programs, which will lead to sequence changes in design if they are not addressed. Most minimization protocols will lead to too much deviation from the original wild-type crystal structure. The relax protocol often shifts the backbone of a protein by more than 1 A RMSD, leading to considerable sequence changes in design. A method that reduces energetic strain while minimizing structural deviation – and the accompanying design sequence changes – would be of considerable use

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Conclusion