Evaluation of mutations on O⁶-methylguanine methyl transferase structure and its interactions: molecular dynamics simulation study

Abstract

O⁶-methylguanine DNA methyl transferase (MGMT) is a significant vehicle for the cellular clearance of alkyl lesions, particularly the methyl group of the O-6 and O-4 positions of guanine and thymine, respectively. Many publications have studied the correlation between polymorphisms in MGMT and susceptibility to various cancers. In the present study, we investigated the consequence of L84F, common single-nucleotide polymorphism, K125E, site-specific mutagenesis, and L84F/K125E on conformation, stability, and behavior of MGMT in the free form and interaction with proliferating cell nuclear antigen (PCNA) and DNA as partners in the biochemical network by using molecular dynamics simulation method. Our results showed that all free variants of MGMT differed from the native form. However, among all free variants of MGMT, the L84F/K125E variant exhibited similar properties compared with the wild-type. In contrast, in complex modes, only amino acid residues of the L84F variant are involved in the interactions with PCNA and DNA somewhat differently relative to the wild-type. Furthermore, L84F SNP showed the highest binding free energy compared to other variants and native forms. These alterations in the amino acids and binding free energy of L84F relative to the native are the reasons for changing its region connection compared to the native form. Therefore, we propose conducting further investigations into the impact of inhibitors or chemotherapeutic agents to assess their effectiveness on MGMT variants compared to the wild-type, aiming to reduce the cost of cancer treatment that will depend on inhibiting native MGMT protein.

Communicated by Ramaswamy H. Sarma

Keywords:

• O⁶-methylguanine-DNA-methyltransferase (MGMT)
• polymorphism
• proliferating cell nuclear antigen (PCNA)
• molecular dynamics simulation
• protein-protein interaction

Acknowledgements

We are grateful to the reviewers and editors, which helped enhance the paper’s quality.

Supplementary information

File supplementary information include Figurers, table to support ‘‘RESULTS’’ sections of this paper.

Disclosure statement

There is no conflict of interest.

Funding

This article was a part of a doctoral dissertation and was funded by the researchers themselves.

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This study did not require material.

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This article was a computational biology study; it did not require an ethical verification code.

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This study was not performed on individuals.

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