Improving the Force Field Description of Tyrosine-Choline Cation-pi Interactions: QM Investigation of Phenol-N(Me)(4)(+) Interactions

Hanif M. Khan, Cedric Grauffel, Ria Broer, Alexander D. MacKerell, Remco W. A. Havenith, Nathalie Reuter*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Scopus)
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Cation-pi interactions between tyrosine amino acids and compounds containing N,N,N-trimethylethanolammonium (N(CH3)(3)) are involved in the recognition of histone tails by chromodomains and in the recognition of phosphatidylcholine (PC) phospholipids by membrane-binding proteins. Yet, the lack of explicit polarization or charge transfer effects in molecular mechanics force fields raises questions about the reliability of the representation of these interactions in biomolecular simulations. Here, we investigate the nature of phenol tetramethylammonium (TMA) interactions using quantum mechanical (QM) calculations, which we also use to evaluate the accuracy of the additive CHARIVIM36 and Drude polarizable force fields in modeling tyrosine-choline interactions. We show that the potential energy surface (PES) obtained using SAPT2+/aug-cc-pVDZ compares well with the large basis-set CCSD(T) PES when TMA approaches the phenol ring perpendicularly. Furthermore, the SAPT energy decomposition reveals comparable contributions from electrostatics and dispersion in phenol-TMA interactions. We then compared the SAPT2+/augcc-pVDZ PES obtained along various approach directions to the corresponding PES obtained with CHARMM, and we show that the force field accurately reproduces the minimum distances while the interaction energies are underestimated. The use of the Drude polarizable force field significantly improves the interaction energies but decreases the agreement on distances at energy minima. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones terms for atom pairs involved in the phenol-TMA cation-pi interactions. This is further shown to improve the correlation between the occupancy of tyrosine-choline cation-pi interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants.

Original languageEnglish
Pages (from-to)5585-5595
Number of pages11
JournalJournal of Chemical Theory and Computation
Issue number11
Publication statusPublished - Nov-2016



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