Improving the Force Field Description of Tyrosine-Choline Cation-π Interactions: QM Investigation of Phenol-N(Me)4+Interactions.
Cation-π 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 CHARMM36 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+/aug-cc-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-π interactions. This is further shown to improve the correlation between the occupancy of tyrosine-choline cation-π interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants.
Department of Molecular Biology, University of Bergen , N-5020 Bergen, Norway.|Computational Biology Unit, Department of Informatics, University of Bergen , N-5020 Bergen, Norway.
Hanif M
HM
Khan
Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
Cédric
C
Grauffel
Ria
R
Broer
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , Baltimore, Maryland 21201, United States.
Alexander D
AD
MacKerell
Ghent Quantum Chemistry Group, Department of Inorganic and Physical Chemistry, Ghent University , 9000 Ghent, Belgium.
Remco W A
RW
Havenith
Department of Molecular Biology, University of Bergen , N-5020 Bergen, Norway.|Computational Biology Unit, Department of Informatics, University of Bergen , N-5020 Bergen, Norway.
Nathalie
N
Reuter
D002412:Cations / Q000737:chemistry; D002794:Choline / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010636:Phenols / Q000737:chemistry*; D011789:Quantum Theory; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry*
D002412:Cations; D008051:Lipid Bilayers; D010636:Phenols; D000644:Quaternary Ammonium Compounds; D012997:Solvents; C039795:trimethylethylammonium; D014443:Tyrosine; D002794:Choline
J Comput Chem. 2004 Jul 15;25(9):1157-74
15116359
Biochim Biophys Acta. 2015 May;1850(5):861-871
25149274
J Comput Chem. 2010 Mar;31(4):671-90
19575467
Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
9944570
J Comput Aided Mol Des. 2000 Feb;14(2):123-34
10721501
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
J Comput Chem. 2009 Jul 30;30(10):1545-614
19444816
J Nutr. 2007 Jun;137(6 Suppl 1):1504S-1508S; discussion 1516S-1517S
17513416
Science. 1991 Aug 23;253(5022):872-9
1678899
J Chem Theory Comput. 2010 Mar 1;6(4):1181-1198
20401166
J Chem Phys. 2014 Mar 7;140(9):094106
24606352
Phys Chem Chem Phys. 2008 May 21;10(19):2616-24
18464976
Biophys J. 2005 Dec;89(6):3985-96
16150973
Biophys J. 2008 May 1;94(9):3393-404
18212019
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10566-71
8855218
Nat Commun. 2015 Nov 18;6:8911
26578293
J Biol Chem. 2013 May 24;288(21):14863-73
23576432
J Am Chem Soc. 2012 Sep 26;134(38):15970-8
22934656
J Gen Physiol. 2007 May;129(5):371-7
17438118
Biophys J. 2015 Apr 21;108(8):1987-96
25902438
J Phys Chem A. 2009 Dec 3;113(48):13628-32
19886621
J Comput Chem. 2005 Dec;26(16):1781-802
16222654
J Chem Phys. 2010 Apr 21;132(15):154104
20423165
Science. 1996 Jan 12;271(5246):163-8
8539615
J Chem Theory Comput. 2012 Nov 13;8(11):4610-23
26605618
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5976-80
9600902
J Comput Chem. 2004 Oct;25(13):1584-604
15264253
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9459-64
10449714
J Phys Chem B. 2010 Mar 4;114(8):2549-64
20136072
J Chem Theory Comput. 2013 Dec 10;9(12):5430-5449
24459460
J Am Chem Soc. 2013 Apr 17;135(15):5740-50
23506313
Proteins. 2014 Jul;82(7):1494-502
24464782
Acc Chem Res. 2013 Apr 16;46(4):1020-8
23020662
Phys Rev A Gen Phys. 1988 Sep 15;38(6):3098-3100
9900728
J Chem Theory Comput. 2012 Jan 10;8(1):182-93
26592880
J Chem Theory Comput. 2009 Jul 14;5(7):1761-6
26610001
Chem Rev. 1997 Aug 5;97(5):1303-1324
11851453
Nature. 2009 Mar 26;458(7237):534-7
19252481
J Phys Chem B. 2013 Sep 5;117(35):10093-102
23924321