title: Molecular recognition in a diverse set of protein-ligand interactions studied with molecular dynamics simulations and end-point free energy calculations.
abstract: End-point free energy calculations using MM-GBSA and MM-PBSA provide a detailed understanding of molecular recognition in protein-ligand interactions. The binding free energy can be used to rank-order protein-ligand structures in virtual screening for compound or target identification. Here, we carry out free energy calculations for a diverse set of 11 proteins bound to 14 small molecules using extensive explicit-solvent MD simulations. The structure of these complexes was previously solved by crystallography and their binding studied with isothermal titration calorimetry (ITC) data enabling direct comparison to the MM-GBSA and MM-PBSA calculations. Four MM-GBSA and three MM-PBSA calculations reproduced the ITC free energy within 1 kcal·mol(-1) highlighting the challenges in reproducing the absolute free energy from end-point free energy calculations. MM-GBSA exhibited better rank-ordering with a Spearman ρ of 0.68 compared to 0.40 for MM-PBSA with dielectric constant (ε = 1). An increase in ε resulted in significantly better rank-ordering for MM-PBSA (ρ = 0.91 for ε = 10), but larger ε significantly reduced the contributions of electrostatics, suggesting that the improvement is due to the nonpolar and entropy components, rather than a better representation of the electrostatics. The SVRKB scoring function applied to MD snapshots resulted in excellent rank-ordering (ρ = 0.81). Calculations of the configurational entropy using normal-mode analysis led to free energies that correlated significantly better to the ITC free energy than the MD-based quasi-harmonic approach, but the computed entropies showed no correlation with the ITC entropy. When the adaptation energy is taken into consideration by running separate simulations for complex, apo, and ligand (MM-PBSAADAPT), there is less agreement with the ITC data for the individual free energies, but remarkably good rank-ordering is observed (ρ = 0.89). Interestingly, filtering MD snapshots by prescoring protein-ligand complexes with a machine learning-based approach (SVMSP) resulted in a significant improvement in the MM-PBSA results (ε = 1) from ρ = 0.40 to ρ = 0.81. Finally, the nonpolar components of MM-GBSA and MM-PBSA, but not the electrostatic components, showed strong correlation to the ITC free energy; the computed entropies did not correlate with the ITC entropy.
authors.affiliation: Indiana University Department of Biochemistry and Molecular Biology, ‡Center for Computational Biology and Bioinformatics, §Department of Chemistry and Chemical Biology (IUPUI), ∥Stark Neurosciences Research Institute, Indiana University School of Medicine , 535 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Liwei
authors.initials: L
authors.lastname: Li
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Hurley
authors.forename: Samy O
authors.initials: SO
authors.lastname: Meroueh
mesh_terms: D000818:Animals; D001665:Binding Sites; D002151:Calorimetry; D030562:Databases, Protein; D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020543:Proteome / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D011506:Proteins; D020543:Proteome; D054852:Small Molecule Libraries
references.citation: J Am Chem Soc. 2006 Oct 4;128(39):12766-77
references.pmid: 17002371
references.citation: Philos Trans A Math Phys Eng Sci. 2005 Aug 15;363(1833):2037-53
references.pmid: 16099765
references.citation: J Chem Inf Model. 2012 Jul 23;52(7):1757-68
references.pmid: 22587354
references.citation: J Comput Aided Mol Des. 2008 Mar-Apr;22(3-4):133-9
references.pmid: 18338228
references.citation: J Phys Chem B. 2006 Sep 21;110(37):18680-7
references.pmid: 16970499
references.citation: J Mol Biol. 2000 Jan 14;295(2):337-56
references.pmid: 10623530
references.citation: Proteins. 1994 Sep;20(1):68-84
references.pmid: 7824524
references.citation: J Chem Inf Model. 2011 Oct 24;51(10):2680-9
references.pmid: 21870864
references.citation: J Comput Chem. 2003 Dec;24(16):1999-2012
references.pmid: 14531054
references.citation: J Mol Biol. 1999 Jan 29;285(4):1735-47
references.pmid: 9917408
references.citation: Proteins. 2004 May 1;55(2):383-94
references.pmid: 15048829
references.citation: Protein Sci. 1998 Jan;7(1):206-10
references.pmid: 9514276
references.citation: Proteins. 2010 Aug 15;78(11):2523-32
references.pmid: 20602360
references.citation: Protein Eng Des Sel. 2009 Sep;22(9):575-86
references.pmid: 19643976
references.citation: Bioorg Med Chem. 2012 Jun 1;20(11):3446-53
references.pmid: 22560835
references.citation: ACS Med Chem Lett. 2010 Aug 12;1(5):229-233
references.pmid: 20824148
references.citation: J Comput Chem. 2002 Dec;23(16):1623-41
references.pmid: 12395429
references.citation: Structure. 2006 Apr;14(4):683-93
references.pmid: 16615910
references.citation: J Chem Inf Model. 2011 Apr 25;51(4):755-9
references.pmid: 21438548
references.citation: Adv Protein Chem. 2003;66:27-85
references.pmid: 14631816
references.citation: J Comput Chem. 2002 Oct;23(13):1244-53
references.pmid: 12210150
references.citation: Biochemistry. 2009 Jan 20;48(2):399-414
references.pmid: 19113835
references.citation: J Med Chem. 2000 Nov 30;43(24):4594-605
references.pmid: 11101351
references.citation: J Biol Chem. 2004 Aug 13;279(33):34665-73
references.pmid: 15152012
references.citation: J Am Chem Soc. 2001 Jun 6;123(22):5221-30
references.pmid: 11457384
references.citation: J Am Chem Soc. 2001 May 2;123(17):3986-94
references.pmid: 11457149
references.citation: J Chem Theory Comput. 2012 Oct 9;8(10):3686-95
references.pmid: 26593013
references.citation: J Comput Aided Mol Des. 2012 May;26(5):569-76
references.pmid: 22350568
references.citation: Chem Biol Drug Des. 2008 Jun;71(6):529-32
references.pmid: 18482338
references.citation: J Chem Inf Model. 2011 Sep 26;51(9):2132-8
references.pmid: 21728360
references.citation: Science. 1995 May 26;268(5214):1144-9
references.pmid: 7761829