Destabilization of the MutSα's Protein-protein Interface Due to Binding to the DNA Adduct Induced by Anticancer Agent Carboplatin Via Molecular Dynamics Simulations

Overview

Journal J Mol Model

Publisher Springer

Specialty Molecular Biology

Date 2013 Sep 25

PMID 24061854

Citations 4

Authors

Lacramioara Negureanu

Freddie R Salsbury Jr

Affiliations

Soon will be listed here.

Abstract

DNA mismatch repair (MMR) proteins maintain genetic integrity in all organisms by recognizing and repairing DNA errors. Such alteration of hereditary information can lead to various diseases, including cancer. Besides their role in DNA repair, MMR proteins detect and initiate cellular responses to certain type of DNA damage. Its response to the damaged DNA has made the human MMR pathway a useful target for anticancer agents such as carboplatin. This study indicates that strong, specific interactions at the interface of MutSα in response to the mismatched DNA recognition are replaced by weak, non-specific interactions in response to the damaged DNA recognition. Data suggest a severe impairment of the dimerization of MutSα in response to the damaged DNA recognition. While the core of MutSα is preserved in response to the damaged DNA recognition, the loss of contact surface and the rearrangement of contacts at the protein interface suggest a different packing in response to the damaged DNA recognition. Coupled in response to the mismatched DNA recognition, interaction energies, hydrogen bonds, salt bridges, and solvent accessible surface areas at the interface of MutSα and within the subunits are uncoupled or asynchronously coupled in response to the damaged DNA recognition. These pieces of evidence suggest that the loss of a synchronous mode of response in the MutSα's surveillance for DNA errors would possibly be one of the mechanism(s) of signaling the MMR-dependent programed cell death much wanted in anticancer therapies. The analysis was drawn from dynamics simulations.

Citing Articles

MutS's Multi-Domain Allosteric Response to Three DNA Damage Types Revealed by Machine Learning.

Melvin R, Thompson W, Godwin R, Gmeiner W, Salsbury Jr F Front Phys. 2020; 5.

PMID: 31938712 PMC: 6959842. DOI: 10.3389/fphy.2017.00010.

Melvin R, Xiao J, Berenhaut K, Godwin R, Salsbury F Phys Rev E. 2018; 98(2-1):023307.

PMID: 30253618 PMC: 6325644. DOI: 10.1103/PhysRevE.98.023307.

Visualizing correlated motion with HDBSCAN clustering.

Melvin R, Xiao J, Godwin R, Berenhaut K, Salsbury Jr F Protein Sci. 2017; 27(1):62-75.

PMID: 28799290 PMC: 5734272. DOI: 10.1002/pro.3268.

Uncovering Large-Scale Conformational Change in Molecular Dynamics without Prior Knowledge.

Melvin R, Godwin R, Xiao J, Thompson W, Berenhaut K, Salsbury Jr F J Chem Theory Comput. 2016; 12(12):6130-6146.

PMID: 27802394 PMC: 5719493. DOI: 10.1021/acs.jctc.6b00757.

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