Using Steered Molecular Dynamic Tension for Assessing Quality of Computational Protein Structure Models

TL;DR

This study demonstrates that steered molecular dynamics tension can effectively assess the quality of protein structure models by correlating stability measures with model accuracy, aiding in model selection.

Contribution

It introduces a computational pulling method to evaluate protein model accuracy, showing that break forces can distinguish near-native structures from less accurate models.

Findings

High break forces correlate with near-native models.

Some near-native models exhibit low peak forces, indicating limitations.

Mechanisms of stability in models were analyzed and discussed.

Abstract

The native structures of proteins, except for notable exceptions of intrinsically disordered proteins, in general take their most stable conformation in the physiological condition to maintain their structural framework so that their biological function can be properly carried out. Experimentally, the stability of a protein can be measured by several means, among which the pulling experiment using the atomic force microscope (AFM) stands as a unique method. AFM directly measures the resistance from unfolding, which can be quantified from the observed force-extension profile. It has been shown that key features observed in an AFM pulling experiment can be well reproduced by computational molecular dynamics simulations. Here, we applied computational pulling for estimating the accuracy of computational protein structure models under the hypothesis that the structural stability would positively correlated with the accuracy, i.e. the closeness to the native, of a model. We used in total 4,929 structure models for 24 target proteins from the Critical Assessment of Techniques of Structure Prediction (CASP) and investigated if the magnitude of the break force, i.e., the force required to rearrange the model structure, from the force profile was sufficient information for selecting near-native models. We found that near-native models can be successfully selected by examining their break forces suggesting that high break force indeed indicates high stability of models. On the other hand, there were also near-native models that had relatively low peak forces. The mechanisms of the stability exhibited by the break forces were explored and discussed.