Methyl-Induced Polarization Destabilizes the Noncovalent Interactions of N-Methylated Lysines

Sanim Rahman, Vered Wineman-Fisher, Péter R. Nagy, Yasmine Al-Hamdani, Alexandre Tkatchenko, Sameer Varma

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Lysine methylation can modify noncovalent interactions by altering lysine's hydrophobicity as well as its electronic structure. Although the ramifications of the former are documented, the effects of the latter remain largely unknown. Understanding the electronic structure is important for determining how biological methylation modulates protein−protein binding, and the impact of artificial methylation experiments in which methylated lysines are used as spectroscopic probes and protein crystallization facilitators. The benchmarked first-principles calculations undertaken here reveal that methyl-induced polarization weakens the electrostatic attraction of amines with protein functional groups – salt bridges, hydrogen bonds and cation-π interactions weaken by as much as 10.3, 7.9 and 3.5 kT, respectively. Multipole analysis shows that weakened electrostatics is due to the altered inductive effects, which overcome increased attraction from methyl-enhanced polarizability and dispersion. Due to their fundamental nature, these effects are expected to be present in many cases. A survey of methylated lysines in protein structures reveals several cases in which methyl-induced polarization is the primary driver of altered noncovalent interactions; in these cases, destabilizations are found to be in the 0.6–4.7 kT range. The clearest case of where methyl-induced polarization plays a dominant role in regulating biological function is that of the PHD1-PHD2 domain, which recognizes lysine-methylated states on histones. These results broaden our understanding of how methylation modulates noncovalent interactions.

Original languageEnglish
Pages (from-to)11005-11014
Number of pages10
JournalChemistry - A European Journal
Volume27
Issue number42
DOIs
StatePublished - 26 Jul 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Funding

The authors acknowledge the use of computer time from Research Computing at USF, UL and the DECI resource SAGA (PRACE NN9914K). The authors are also grateful to the National Institutes of Health for partially funding this study through grants no. R01GM118697 and R01‐AA026082. P.R.N. is grateful for financial support of NKFIH, grant no. KKP126451, ÚNKP‐20‐5 New National Excellence Program of the Ministry for Innovation and Technology and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors acknowledge the use of computer time from Research Computing at USF, UL and the DECI resource SAGA (PRACE NN9914K). The authors are also grateful to the National Institutes of Health for partially funding this study through grants no. R01GM118697 and R01-AA026082. P.R.N. is grateful for financial support of NKFIH, grant no. KKP126451, ÚNKP-20-5 New National Excellence Program of the Ministry for Innovation and Technology and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.

FundersFunder number
National Institutes of HealthR01GM118697
National Institute on Alcohol Abuse and AlcoholismR01AA026082
University of San Francisco
Magyar Tudományos Akadémia
Nemzeti Kutatási Fejlesztési és Innovációs HivatalKKP126451
Innovációs és Technológiai Minisztérium

    Keywords

    • electronic polarization
    • inductive effects
    • lysine methylation
    • noncovalent interactions
    • quantum chemistry

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