Evaluating the significance of contact maps in low-homology protein modeling using contact-assisted threading

Abstract

AbstractThe development of improved threading algorithms for remote homology modeling is a critical step forward in template-based protein structure prediction. We have recently demonstrated the utility of contact information to boost protein threading by developing a new contact-assisted threading method. However, the nature and extent to which the quality of a predicted contact map impacts the performance of contact-assisted threading remains elusive. Here, we systematically analyze and explore this interdependence by employing our newly-developed contact-assisted threading method over a large-scale benchmark dataset using predicted contact maps from four complementary methods including direct coupling analysis (mfDCA), sparse inverse covariance estimation (PSICOV), classical neural network-based meta approach (MetaPSICOV), and state-of-the-art ultra-deep learning model (RaptorX). Experimental results demonstrate that contact-assisted threading using high-quality contacts having the Matthews Correlation Coefficient (MCC) ≥ 0.5 improves threading performance in nearly 30% cases, while low-quality contacts with MCC <0.35 degrades the performance for 50% cases. This holds true even in CASP13 dataset, where threading using high-quality contacts (MCC ≥ 0.5) significantly improves the performance of 22 instances out of 29. Collectively, our study uncovers the mutual association between the quality of predicted contacts and its possible utility in boosting threading performance for improving low-homology protein modeling.