Document Type

Article

Publication Date

2021

DOI

10.3389/fmolb.2021.696609

Publication Title

Frontiers in Molecular Biosciences

Volume

8

Pages

696609 (1-13)

Abstract

We employed mutual information (MI) analysis to detect motions affecting the mechanical resistance of the human-engineered protein Top7. The results are based on the MI analysis of pair contact correlations measured in steered molecular dynamics (SMD) trajectories and their statistical dependence on global unfolding. This study is the first application of the MI analysis to SMD forced unfolding, and we furnish specific SMD recommendations for the utility of parameters and options in the TimeScapes package. The MI analysis provided a global overview of the effect of perturbation on the stability of the protein. We also employed a more conventional trajectory analysis for a detailed description of the mechanical resistance of Top7. Specifically, we investigated 1) the hydropathy of the interactions of structural segments, 2) the H2O concentration near residues relevant for unfolding, and 3) the changing hydrogen bonding patterns and main chain dihedral angles. The results show that the application of MI in the study of protein mechanical resistance can be useful for the engineering of more resistant mutants when combined with conventional analysis. We propose a novel mutation design based on the hydropathy of residues that would stabilize the unfolding region by mimicking its more stable symmetry mate. The proposed design process does not involve the introduction of covalent crosslinks, so it has the potential to preserve the conformational space and unfolding pathway of the protein.

Comments

© 2021 Perišić and Wriggers.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 License (CC BY 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Original Publication Citation

Perišić, O., & Wriggers, W. (2021). Mechanism for the unfolding of the TOP7 protein in steered molecular dynamics simulations as revealed by mutual information analysis. Frontiers in Molecular Biosciences, 8, 1-13, Article 696609. https://doi.org/10.3389/fmolb.2021.696609

ORCID

0000-0001-5326-3152 (Wriggers)

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