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Base flipping mechanism and binding strength of methyl-damaged DNA during the interaction with AGT

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Abstract

Methyl damage to DNA bases is common in the cell nucleus. O6-alkylguanine-DNA alkyl transferase (AGT) may be a promising candidate for direct damage reversal in methylated DNA (mDNA) at the O6 point of the guanine. Indeed, atomic-level investigations in the contact region of AGT-DNA complex can provide an in-depth understanding of their binding mechanism, allowing to evaluate the silico-drug nature of AGT and its utility in removing methyl damage in DNA. In this study, molecular dynamics (MD) simulation was utilized to examine the flipping of methylated nucleotide, the binding mechanism between mDNA and AGT, and the comparison of binding strength prior and post methyl transfer to AGT. The study reveals that methylation at the O6 atom of guanine weakens the hydrogen bond (H-bond) between guanine and cytosine, permitting for the flipping of such nucleotide. The formation of a H-bond between the base pair of methylated nucleotide (i.e., cytosine) and the intercalated arginine of AGT also forces the nucleotide to rotate. Following that, electrostatics and van der Waals contacts as well as hydrogen bonding contribute to form the complex of DNA and protein. The stronger binding of AGT with DNA before methyl transfer creates the suitable condition to transfer methyl adduct from DNA to AGT.

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Acknowledgements

We sincerely thank Professor Alexander D. MacKerell Jr from Computer-Aided Drug Design Center, School of Pharmacy, University of Maryland, USA for providing force field parameters for methylated residues. The authors acknowledge support from the Research Coordination and Development Council (RCDC) of Tribhuvan University Grants number TU-NPAR-077/78-ERG 14.

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  1. Central Department of Physics, Tribhuvan University, Kathmandu, Nepal

    Rajendra Prasad Koirala & Narayan Prasad Adhikari

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  1. Rajendra Prasad Koirala
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Rajendra Prasad Koirala conducted the research work under the supervision of Narayan Prasad Adhikari.

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Correspondence to Narayan Prasad Adhikari.

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This is a theoretical work. The work is not intended by any financial or any other personal interest; rather it is solely research-motivated.

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Highlights

• Triple hydrogen bonds of guanine with cytosine is reduced to a double hydrogen bonds due to methylation at O6 atom, which facilitates to flip out the methylated guanine.

• Hydrogen bonding, electrostatic and van der Waals interaction basically contribute to bind at the interfacial region of DNA and AGT.

• Unbinding force is greater in mDNA-AGT complex than the DNA-mAGT that exhibits the degradation the binding strength after methylation repair in DNA.

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Koirala, R.P., Adhikari, N.P. Base flipping mechanism and binding strength of methyl-damaged DNA during the interaction with AGT. J Biol Phys 50, 71–87 (2024). https://doi.org/10.1007/s10867-023-09649-9

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