title: Evaluation of Density Functionals, SCC-DFTB, Neglect of Diatomic Differential Overlap (NDDO) Models and Molecular Mechanics Methods for Prolyl-Leucyl-Glycinamide (PLG) and Structural Derivatives.
abstract: Prolyl-leucyl-glycinamide (PLG) is a unique endogenous peptide that modulates dopamine receptor subtypes of the D(2) receptor family within the CNS. We seek to elucidate the structural basis and molecular mechanism by which PLG and its analogues modulate dopamine receptors, toward the development of new therapeutics to treat Parkinson's disease, tardive dyskinesia and schizophrenia. As a first step toward establishing a validated protocol for accurate computational modeling of PLG and associated peptidomimetic analogues, we evaluated the accuracy of density functional theory (DFT), wavefunction theory (WFT), and molecular mechanics (MM) calculations for PLG and for a library of structurally related small molecules. We first tested twelve local and nonlocal density functionals, Hartree-Fock (HF) theory, four "semiempirical" methods of the neglect of diatomic differential overlap (NDDO) type, and one self-consistent-charge nonorthogonal tight-binding (SCC-DFTB) method as implemented in two software suites, against coupled-cluster benchmark geometries for 4-methylthiazolidine, a small molecule that comprises key structural features present in our PLG analogue library. DFT and HF calculations were done with the MG3S augmented polarized triple-zeta basis set. We find that for 4-methylthiazolidine bond distances, DFT significantly outperforms NDDO, and both SCC-DFTB versions we evaluated perform worse than HF theory and are less accurate than 83% of the density functionals tested. The top five functionals for 4-methylthiazolidine were M05-2X, mPW1PW, B97-2, M06-2X, and PBEh, with mean unsigned errors (MUEs) in bond length of 0.0017, 0.0020, 0.0023, 0.0025 and 0.0027 Å, respectively. The widely used B3LYP functional ranked 11(th) out of twelve functionals evaluated, slightly below SCC-DFTB, and is significantly less accurate for 4-methylthiazolidine bond distances (MUE = 0.0095 Å) than the best local functional (M06-L, MUE = 0.0030 Å), which is far less computationally costly. Based on that initial analysis, we obtained new M05-2X benchmark geometric parameters for PLG and a library of eleven peptidomimetic derivatives, which we in turn used to examine the accuracy of thirty-four popular molecular mechanics (MM) force fields, four NDDO approaches, and SCC-DFTB for the full compound structures. Here, we found that ∼70% of the MM force fields tested superior to the best semiempirical and SCC-DFTB codings. Moreover, AMBER-type force fields proved most accurate among MM methods for this class of small-molecule peptidomimetics; the AMBER-type methods comprised eight out of the top ten molecular mechanics options we tested.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 717 Delaware St SE, Minneapolis, Minnesota 55414-2959;
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wood
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Young-Dixon
authors.forename: Abhrajeet
authors.initials: A
authors.lastname: Roy
authors.forename: Bryant C
authors.initials: BC
authors.lastname: Gay
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Amin
references.citation: J Chem Theory Comput. 2006 Mar;2(2):364-82
references.pmid: 26626525
references.citation: J Comput Chem. 2004 Aug;25(11):1400-15
references.pmid: 15185334
references.citation: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5350-4
references.pmid: 16593959
references.citation: Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
references.pmid: 9944570
references.citation: J Med Chem. 2006 Jan 12;49(1):307-17
references.pmid: 16392815
references.citation: J Comput Chem. 1999 May;20(7):720-729
references.pmid: 34376030
references.citation: J Comput Chem. 1986 Apr;7(2):230-252
references.pmid: 29160584
references.citation: Phys Rev Lett. 1996 Oct 28;77(18):3865-3868
references.pmid: 10062328
references.citation: J Chem Inf Model. 2006 Jul-Aug;46(4):1775-83
references.pmid: 16859309
references.citation: Biochemistry. 1988 Jul 12;27(14):5246-57
references.pmid: 3167044
references.citation: J Chem Phys. 2006 Nov 21;125(19):194101
references.pmid: 17129083
references.citation: Proteins. 1988;4(1):31-47
references.pmid: 3054871
references.citation: Annu Rev Pharmacol Toxicol. 1993;33:281-307
references.pmid: 8494342
references.citation: J Comput Chem. 1999 May;20(7):730-748
references.pmid: 34376036
references.citation: Methods Find Exp Clin Pharmacol. 1983;5(4):203-33
references.pmid: 6136640
references.citation: Phys Rev B Condens Matter. 1995 May 15;51(19):12947-12957
references.pmid: 9978089
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1982;6(4-6):365-8
references.pmid: 6298884
references.citation: Pharmacol Res Commun. 1983 Jan;15(1):41-51
references.pmid: 6131441
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: J Phys Chem A. 2007 Jul 5;111(26):5678-84
references.pmid: 17567110
references.citation: J Biomol Struct Dyn. 1999 Feb;16(4):845-62
references.pmid: 10217454
references.citation: J Med Chem. 2001 Nov 8;44(23):3849-55
references.pmid: 11689071
references.citation: J Am Chem Soc. 1974 Aug 21;96(17):5319-27
references.pmid: 4851860
references.citation: Biochemistry. 1988 Sep 20;27(19):7176-80
references.pmid: 3207668
references.citation: J Chem Theory Comput. 2009 May 12;5(5):1254-65
references.pmid: 26609716
references.citation: J Biomol Struct Dyn. 1995 Oct;13(2):201-18
references.pmid: 8579782
references.citation: J Chem Inf Model. 2006 Sep-Oct;46(5):2104-9
references.pmid: 16995741
references.citation: J Phys Chem A. 2005 Mar 10;109(9):2012-8
references.pmid: 16833536
references.citation: J Chem Theory Comput. 2008 Jan;4(1):75-85
references.pmid: 26619981
references.citation: Theochem. 2008;861(1-3):68-73
references.pmid: 19122761
references.citation: J Am Chem Soc. 1974 Aug 21;96(17):5327-35
references.pmid: 4851861