Developing optimal non-linear scoring function for protein design

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.