Improved contact prediction in proteins: Using pseudolikelihoods to infer Potts models

TL;DR

This paper introduces a pseudolikelihood-based method for inferring Potts models to improve contact prediction in proteins, outperforming previous mean-field approaches and validated against known crystal structures.

Contribution

The paper presents a novel pseudolikelihood approach for direct-coupling analysis in proteins, enhancing accuracy over existing methods.

Findings

Pseudolikelihood method outperforms mean-field techniques in contact prediction.

Modified coupling score improves inference accuracy.

Validated results using known protein crystal structures.

Abstract

Spatially proximate amino acids in a protein tend to coevolve. A protein's three-dimensional (3D) structure hence leaves an echo of correlations in the evolutionary record. Reverse engineering 3D structures from such correlations is an open problem in structural biology, pursued with increasing vigor as more and more protein sequences continue to fill the data banks. Within this task lies a statistical inference problem, rooted in the following: correlation between two sites in a protein sequence can arise from firsthand interaction but can also be network-propagated via intermediate sites; observed correlation is not enough to guarantee proximity. To separate direct from indirect interactions is an instance of the general problem of inverse statistical mechanics, where the task is to learn model parameters (fields, couplings) from observables (magnetizations, correlations, samples) in large systems. In the context of protein sequences, the approach has been referred to as direct-coupling analysis. Here we show that the pseudolikelihood method, applied to 21-state Potts models describing the statistical properties of families of evolutionarily related proteins, significantly outperforms existing approaches to the direct-coupling analysis, the latter being based on standard mean-field techniques. This improved performance also relies on a modified score for the coupling strength. The results are verified using known crystal structures of specific sequence instances of various protein families. Code implementing the new method can be found at http://plmdca.csc.kth.se/.