Document Type

Article

Article Version

Pre-print

Publication Date

2-2-2024

Abstract

Deficiency of MutSbeta protein has been proven to be a cause of Lynch Syndrome, which leads to hereditary colorectal cancer. In the absence of MutSbeta, or the energy source to initiate the conformational change of MutSbeta, the DNA repair pathway would not detect the DNA base pairing errors resulting in a failure to proceed. To examine the essential role of MutSbeta and the interface between MutSbeta and a mismatched DNA strand, 500ns of molecular dynamics simulations were performed and the results were compared with the controls. It is found that during the first 100ns, the outermost domain of MutSbeta (chain BP4) gets hold of the DNA, and the inner domains (AP1 and BP1) prepare to scan the DNA strand. An RMSD of 5-7Å for the control MutSbeta compared to 3-6.5Å in the presence of a mismatched DNA indicate that starting ∼75ns, MutSbeta stabilizes and initiates the scanning of the mismatched DNA. The reduction of the distance between the two biomolecules by ∼16Å, increase of Van der Waals energies by ∼75 kCal/mol and a crucial role played by the interfacial water molecules and their hydrogen bonds during the next 100ns also supports the manipulative nature and initiation of scanning by MutSbeta.

Comments

© 2024 by the authors. This article is an open access pre-print distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Publication Title

BioRxiv

Published Citation

Devlin, J., Madigan, J., & Macwan, I. Onset of Mismatch Repair by the Human Mismatch Repair Protein, MutSbeta for a Biosensing Device. BioRxiv, 2024.01.31.578329 (2024). https://doi.org/10.1101/2024.01.31.578329

DOI

10.1101/2024.01.31.578329

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