Prediction of Peptide Binding to Major Histocompatibility II Receptors with Molecular Mechanics and Semi-Empirical Quantum Mechanics Methods

Sarah Aldulaijan, James A Platts


Methods for prediction of the binding of peptides to major histocompatibility complex (MHC) II receptors are examined, using literature values of IC50 as a benchmark. Two sets of IC50 data for closely structurally related peptides based on hen egg lysozyme (HEL) and myelin basic protein (MBP) are reported first. This shows that methods based on both molecular mechanics and semi-empirical quantum mechanics can predict binding with good-to-reasonable accuracy, as long as a suitable method for estimation of solvation effects is included. A more diverse set of 22 peptides bound to HLA-DR1 provides a tougher test of such methods, especially since no crystal structure is available for these peptide-MHC complexes. We therefore use sequence based methods such as SYFPEITHI and SVMHC to generate possible binding poses, using a consensus approach to determine the most likely anchor residues, which are then mapped onto the crystal structure of an unrelated peptide bound to the same receptor. This analysis shows that the MM/GBVI method performs particularly well, as does the AMBER94 forcefield with Born solvation model. Indeed, MM/GBVI can be used as an alternative to sequence based methods in generating binding poses, leading to still better accuracy.


major histocompatibility complex; molecular mechanics; quantum mechanics; density functional theory


Aldulaijan S & Platts JA 2010 Theoretical prediction of a peptide binding to major histocompatibility complex II Journal of Molecular Graphics and Modelling 29 240-245.

Anisimov V, Ziemys A, Kizhake S, Yuan Z, Natarajan A & Cavasotto C 2011 Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1. Journal of Computer-Aided Molecular Design 25 1071-1084.

Anisimov VM & Cavasotto CN 2011 Quantum mechanical binding free energy calculation for phosphopeptide inhibitors of the Lck SH2 domain. Journal of Computational Chemistry 32 2254-2263.

Cerny J & Hobza P 2007 Non-covalent interactions in biomacromolecules Physical Chemistry Chemical Physics 9 5291-5303.

Cheng Y & Prusoff W 1973 Relationship between the inhi- bition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22 3099-3108.

Donnes P & Elofsson A 2002 Prediction of MHC class I binding peptides using SVMHC. bioinformatics 3.

Donnes P & Kohlbacher O 2006 SVMHCL a server for prediction for MHC-binding peptides. Nucleic acids research 34 web server issue.

Dorfman DD & Alf E 1969 Maximum likelihood estimation of parameters of signal detection theory and determination of confidence intervals - rating method data. Journal of Mathematical Psychology 6 487-496.

Eistner M, Hobza P, Frauenheim T, Suhai S & Kaxiras E 2001 Hydrogen bonding and stacking interactions of nucleic base pairs: A density-functional-theory based treatment. Journal of Chemical physics 114 5149-5155.

Gohlke H, Kiel C & Case DA 2003 Insights into Protein–Protein Binding by Binding Free Energy Calculation and Free Energy Decomposition for the Ras–Raf and Ras–RalGDS Complexes. Journal of Molecular Biology 330 891 -913.

Grimme S 2004 Accurate description of van der waals complexes by density functional theory including empirical corrections. Journal of Computational Chemistry 25 1463- 1473.

Harrison LC, Honeyman MC, Termbleau S, Gregori S, Gallazzi F, Augstein P, Brusic V, Hammer J & Adorini L 1997 A Peptide-binding Motif for I-Ag7, the Class II Major Histocompatibility Complex (MHC) Molecule of NOD and Biozzi AB/H Mice. Journal of Experimental Medicine 185 1013-1021.

Hobza P, Kabelac M, Sponer J, Mejzlik P & Vondrasek J 1997 Performance of empirical potentials (AMBER, CFF95, CVFF, CHARMM, OPLS, POLTEV), semiempirical quantum chemical methods (AM1, MNDO/M, PM3), and ab initio Hartree-Fock method for interaction of DNA bases: Comparison with nonempirical beyond Hartree-Fock results Journal of Computational Chemistry 18 1136-1150.

Jalkanen KJ, Elstner M & Suhai S 2004 Amino acids and small peptides as building blocks for proteins: comparative theoretical and spectroscopic studies Journal of Molecular Structure: THEOCHEM 675 61-77.

Jurecka P, Cerny J, Hobza P & Salahub D 2006a Density functional theory augmented with empirical dispersion term. Interaction energies and geometries of 80 noncovalent complexes compared with Ab initio quantum mechanics calculations. Journal of Computational Chemistry 28 555-569.

Jurecka P, Sponer J, Cerny J & Hobza P 2006b Benchmark database of accurate (MP2 and CCSD(T) complete basis set limit) interaction energies for small model complexes, DNA base pairs, and amino acid pairs. Physical Chemistry Chemical Physics 8 1985-1993.

Klamt A 1994 Conductor-like Screening Model for Real Solvent: A New Approach to the Quantitative Calculation of Solvation Phenomena. Journal of Physical chemistry 99 2224-2235.

Klamt A & Schuurmann G 1993 COSMO: A new approch to dielectric screening in solvent with explicit experessions for the screening energy and its gradient. Journal of Chemical Society Perkin Transactions 2 799-805.

Korth M 2010 Third-Generation Hydrogen-Bonding Corrections for Semiempirical QM Methods and Force Fields Journal of Chemical Theory and Computation 6 3808-3816.

Korth M, Pitonak M, Rezac J & Hobza P 2010a A Transferable H-bonding correction for semiempirical quantum-chemical methods. Journal of chemical theory and computation 6 344-352.

Korth M, Pitonak M, Rezac J & Hobza P 2010b A Transferable H-bonding correction for semiempirical quantum-chemical methods. Journal of chemical theory and computation 6 344-352.

Krogsgaard M, Wucherpfenning KW, Canella B, Hansen BE, Svejgraad A, Pyrdol J, Ditzel H, Raine C, Engberg J & Fugger L 2000 Visualization of Myelin Basic Protein (MBP) T Cell Epitopes in Multiple Sclerosis using a Monoclonal Antibody Specfic for the Human Histocompatibility Leukocyte Antigen (HILA)-DR2-MBP 85-99 Complex. Journal of Experimental Medicine 191 1395-1412.

Labute P 2008a The Generalized Born/Volume Integral Implicit Solvent Model: Estimation of the Free Energy of Hydration Using London Dispersion Instead of Atomic Surface Area. Journal of Computational Chemistry 29 1693-1698.

Labute P 2008b The Generalized Born/Volume Integral Implicit Solvent Model: Estimation of the Free Energy of Hydration Using London Dispersion Instead of Atomic Surface Area. Journal of computaional chemistry 29 1693-1698.

Mantzourani E, Laimou D, Matsoukas MT & Tselios T 2008 Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 7 294-306

Mantzourani ED, Mavromoustakos TM, Platts JA, Matsoukas JM & Tselios TV 2005 Structural requirements for binding of Myelin Basic Protein (MBP) peptides to MHC II: Effects on immune regulation. Current Medicinal Chemistry 12 1521-1535

McNamara JP & Hillier IH 2007 Semi-empirical molecular orbital methods including dispersion corrections for the accurate prediction of the full range of intermolecular interactions in biomolecules Physical Chemistry Chemical Physics 9 2362-2370

Metz CE, Herman BA & Shen J-H 1998 Maximum-likelihood estimation of ROC curves from continuously-distributed data. Stat. Med. Journals 17 1033-1053.

Meyer EA, Castellano RK & Francois Diederich 2003 Interactions with Aromatic Rings in Chemical and Biological Recoqnition. Angewandte chemie 42 1210-1250

Murthy VL & Stern LJ 1997 The class II MHC protein HLA -DR1 in complex with an endogenous peptide: implications for the structural basis of the specificity of peptide binding. Structure 5 1385-1397.

Paton RS & Goodman JM 2009 Hydrogen Bonding and pistacking: How reliable are Force Fields? A critical evaluation of force field descriptions of non-bonded interactions Journal of Chemical Information and Modelling 49 944- 955.

Puzyn T, Suzuki N, Heranczyk M & Rak J 2008 Calculation of Quantum-Mechanical Descriptor for QSPR at the DFT level: Is it Necessary? Journal of chemical information and modeling 48 1174-1180.

Qiu D, Shenkin PS, Hollinger FP & Still WC 1997 The GB/ SA Continuum Model for Solvation. A Fast Analytical Method for the Calculation of Approximate Born Radii. Journal of physical chemistry A 101 3005-3014.

Rezac J, Fanfrlik J, Salahub D & Hobza P 2009 Semiempirical Quantum Chemical PM6 Method Augmented by Dispersion and H-bonding Correction Terms Reliably describes Various Types of Noncovalent Complexes. Journal of Chemical Theory and Computation 5 1749-1760.

Rocha GB, Freire RO, Simas AM & Stewart JJP 2006 RM1: A Reparameterization of AM1 for H, C, N, O, P, S, F, Cl, and I. Journal of Computational Chemistry 27 1101-1111.

Rommensee H-G, Bachmann J, Emmerich NP, Bachor OA & Stevanovic S 1999 SYFPEITHI: database for MHC ligands and peptides motifs. Immunogenetics. 50 213-219.

Sharma R, McNamara JP, Raju RK, Vincent MA, Hillier IH & Morgado CA 2008 The interaction of carbohydrates and amino acids with aromatic systems studied by density functional and semi-empirical molecular orbital calculations with dispersion corrections Physical Chemistry Chemical Physics 10 2767-2774

Southwood S, Sidney J, Kondo A, Guercio M-Fd, Appella E, Hoffman S, Kubo RT, Chesnut RW, Gery HM & Sette A 1998 Several common HLA-DR types share largely overlapping peptide binding repertoires. The Journal of Immunology 160 3363-3373.

Stewart JJP 2007 Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements. Journal of Molecular modeling 13 1173-1213.

Still WC, Tempczyk A, Hawley RC & Hendrickson T 1990 Semianalytical treatment of solvation for molecular mechanics and dynamics. Journal of the American Chemical Society 112 6127-6129.

Tajkhorshid EJ, K. J; Suhai, S 1998 Structure and Vibrational Spectra of the Zwitterion l-Alanine in the Presence of Explicit Water Molecules:? A Density Functional Analysis Journal of Physical chemistry B 102 5899-5913.

Tsai CS 2002 An introduction to computational biochemistry.

Tuttle T & Thiel W 2008 OMx-D: semiempirical methods with orthogonalization and dispersion corrections. Implementation and biochemical application. Physical Chemistry Chemical Physics 10 2159-2166.

Wang W & Kollman PA 2000 Free Energy Calculations on Dimer Stability of the HIV Protease using Molecular Dynamics and a Continuum Solvent Model. Journal of Molecular Biology 303 567-582.

Wearsch PA & Cresswell P 2008 The quality control of MHC class I peptide loading Current Opinion in Cell Biology 20 624-631

Zhao Y & Truhlar D 2007 Density functionals for noncovalent interaction energies of biological importance Journal of Chemical Theory and Computation 3 289-300

Zoete V, Irving M & Michielin O 2010 MM-GBSA binding free energy decomposition and T cell receptor engineering. Journal of Molecular Recognition. 23 142-152.

Zoete V & Michielin O 2007 Comparison between computational alanine scanning and per-residue binding free energy decomposition for protein-protein association using MM-GBSA: application to the TCR-p-MHC complex. Pro- teins 67 1026-1047.

Full Text: PDF


  • There are currently no refbacks.

Copyright © 2021 Journal of Molecular Biochemistry