Developing optimal non-linear scoring function for protein design.

Changyu Hu; Xiang Li; Jie Liang

doi:10.1093/bioinformatics/bth369

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Developing optimal non-linear scoring function for protein design.

Changyu Hu·Xiang Li·Jie Liang

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Abstract

UNLABELLED: Motivation. Protein design aims to identify sequences compatible with a given protein fold but incompatible to any alternative folds. To select the correct sequences and to guide the search process, a design scoring function is critically important. Such a scoring function should be able to characterize the global fitness landscape of many proteins simultaneously. RESULTS: To find optimal design scoring functions, we introduce two geometric views and propose a formulation using a mixture of non-linear Gaussian kernel functions. We aim to solve a simplified protein sequence design problem. Our goal is to distinguish each native sequence for a major portion of representative protein structures from a large number of alternative decoy sequences, each a fragment from proteins of different folds. Our scoring function discriminates perfectly a set of 440 native proteins from 14 million sequence decoys. We show that no linear scoring function can succeed in this task. In a blind test of unrelated proteins, our scoring function misclassfies only 13 native proteins out of 194. This compares favorably with about three-four times more misclassifications when optimal linear functions reported in the literature are used. We also discuss how to develop protein folding scoring function.

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Algorithms Artificial Intelligence Computer Simulation Drug Design Models, Chemical Models, Molecular Nonlinear Dynamics Protein Conformation Protein Folding Proteins Sequence Alignment Sequence Analysis, Protein Structure-Activity Relationship Comparative Study Evaluation Study Journal Article Research Support, U.S. Gov't, Non-P.H.S.Validation Study

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Changyu Hu, Xiang Li, Jie Liang. 2004-06-24. Developing optimal non-linear scoring function for protein design.. https://doi.org/10.1093/bioinformatics%2Fbth369

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