QUANTUM CALCULATION OF PROTEIN SOLVATION AND PROTEIN–LIGAND BINDING FREE ENERGY FOR HIV-1 PROTEASE/WATER COMPLEX

HIV-1 protease (PR) is a primary target for anti-HIV therapeutics. A well conserved water molecule, denoted as W301, is found in almost all the crystallographic structures of PR/inhibitor complexes and it plays an important role in PR/inhibitor binding. As the PR/inhibitor interaction depends on the ionization state of the cleavage site which contains an aspartyl dyad (Asp25/Asp25′), the determination of the protonation states of aspartyl dyad in PR may be essential for drug design. In this study, a linear scaling quantum mechanical method, molecular fragmentation with conjugate caps (MFCC), is used for interaction study of PR/ABT-538 and W301 at four different monoprotonation states of the Asp25/Asp25′. Combined method of MFCC and conductor-like polarizable continuum model (CPCM) is applied in binding affinity calculation for four minimum energy structures which are extracted from four different molecular dynamics trajectories corresponding to four different monoprotonation states of Asp25/Asp25′. Our result is in good agreement with previous result obtained by FEP/TI method, showing that the conserved W301 contributes significantly to the binding free energy of PR/ABT-538 complex and different protonation states of Asp25/Asp25′ have significant impact on the binding free energy contribution from W301.

[1]  Arieh Warshel,et al.  Polarizable Force Fields:  History, Test Cases, and Prospects. , 2007, Journal of chemical theory and computation.

[2]  Paul G. Mezey,et al.  Ab Initio-Quality Electrostatic Potentials for Proteins: An Application of the ADMA Approach , 2002 .

[3]  John Z. H. Zhang,et al.  Fully quantum mechanical energy optimization for protein–ligand structure , 2004, J. Comput. Chem..

[4]  Irwin D Kuntz,et al.  Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods. , 2003, Biopolymers.

[5]  Peter A. Kollman,et al.  AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules , 1995 .

[6]  G. Scuseria,et al.  Gaussian 03, Revision E.01. , 2007 .

[7]  P. Kollman,et al.  Computational Alanine Scanning To Probe Protein−Protein Interactions: A Novel Approach To Evaluate Binding Free Energies , 1999 .

[8]  J. H. Zhang,et al.  Quantum study of HIV-1 protease-bridge water interaction. , 2007, The Journal of chemical physics.

[9]  Nan Jiang,et al.  Electrostatic field-adapted molecular fractionation with conjugated caps for energy calculations of charged biomolecules. , 2006, The Journal of chemical physics.

[10]  Ye Mei,et al.  A new quantum method for electrostatic solvation energy of protein. , 2006, The Journal of chemical physics.

[11]  W. L. Jorgensen,et al.  Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method. , 1997, Journal of medicinal chemistry.

[12]  P A Kollman,et al.  An analysis of the interactions between the Sem-5 SH3 domain and its ligands using molecular dynamics, free energy calculations, and sequence analysis. , 2001, Journal of the American Chemical Society.

[13]  S. Carr,et al.  Human immunodeficiency virus-1 protease. 1. Initial velocity studies and kinetic characterization of reaction intermediates by 18O isotope exchange. , 1991, Biochemistry.

[14]  Michael A Collins,et al.  Accuracy and efficiency of electronic energies from systematic molecular fragmentation. , 2006, The Journal of chemical physics.

[15]  J. Aqvist,et al.  A new method for predicting binding affinity in computer-aided drug design. , 1994, Protein engineering.

[16]  B. Roux,et al.  Calculation of absolute protein-ligand binding free energy from computer simulations. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  John Z H Zhang,et al.  Quantum mechanical map for protein-ligand binding with application to beta-trypsin/benzamidine complex. , 2004, The Journal of chemical physics.

[18]  John Z H Zhang,et al.  An efficient approach for ab initio energy calculation of biopolymers. , 2005, The Journal of chemical physics.

[19]  B. Kuhn,et al.  Validation and use of the MM-PBSA approach for drug discovery. , 2005, Journal of medicinal chemistry.

[20]  John Z. H. Zhang,et al.  FULL AB INITIO COMPUTATION OF PROTEIN-WATER INTERACTION ENERGIES , 2004 .

[21]  D. Case,et al.  Proton binding to proteins: pK(a) calculations with explicit and implicit solvent models. , 2004, Journal of the American Chemical Society.

[22]  Kazuo Kitaura,et al.  On the accuracy of the 3-body fragment molecular orbital method (FMO) applied to density functional theory , 2004 .

[23]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[24]  Yuto Komeiji,et al.  Fragment molecular orbital method: analytical energy gradients , 2001 .

[25]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[26]  Emilio Gallicchio,et al.  Linear Interaction Energy (LIE) Models for Ligand Binding in Implicit Solvent:  Theory and Application to the Binding of NNRTIs to HIV-1 Reverse Transcriptase. , 2007, Journal of chemical theory and computation.

[27]  John Z. H. Zhang,et al.  Molecular fractionation with conjugate caps for full quantum mechanical calculation of protein-molecule interaction energy , 2003 .

[28]  T. Bhat,et al.  Bound Water Molecules at the Interface between the HIV-1 Protease and a Potent Inhibitor, KNI-272, Determined by NMR , 1996 .

[29]  E. Padlan,et al.  Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Ray Luo,et al.  How well does Poisson-Boltzmann implicit solvent agree with explicit solvent? A quantitative analysis. , 2006, The journal of physical chemistry. B.

[31]  P. Kollman,et al.  Continuum Solvent Studies of the Stability of DNA, RNA, and Phosphoramidate−DNA Helices , 1998 .

[32]  J. Kirkwood.  Statistical Mechanics of Fluid Mixtures , 1935 .

[33]  Yutaka Akiyama,et al.  Fragment molecular orbital method: application to polypeptides , 2000 .

[34]  Wei Li,et al.  An efficient fragment-based approach for predicting the ground-state energies and structures of large molecules. , 2005, Journal of the American Chemical Society.

[35]  Yang,et al.  Direct calculation of electron density in density-functional theory. , 1991, Physical review letters.

[36]  P A Kollman,et al.  Structure and thermodynamics of RNA-protein binding: using molecular dynamics and free energy analyses to calculate the free energies of binding and conformational change. , 2000, Journal of molecular biology.

[37]  John Z H Zhang,et al.  New Advance in Computational Chemistry:  Full Quantum Mechanical ab Initio Computation of Streptavidin-Biotin Interaction Energy. , 2003, The journal of physical chemistry. B.

[38]  Peter A. Kollman,et al.  FREE ENERGY CALCULATIONS : APPLICATIONS TO CHEMICAL AND BIOCHEMICAL PHENOMENA , 1993 .

[39]  H. Scheraga,et al.  Energy parameters in polypeptides. 9. Updating of geometrical parameters, nonbonded interactions, and hydrogen bond interactions for the naturally occurring amino acids , 1983 .

[40]  R. Zwanzig.  High‐Temperature Equation of State by a Perturbation Method. I. Nonpolar Gases , 1954 .

[41]  Chao-Yie Yang,et al.  Binding free energy contributions of interfacial waters in HIV-1 protease/inhibitor complexes. , 2006, Journal of the American Chemical Society.

[42]  Wei Zhang,et al.  A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations , 2003, J. Comput. Chem..

[43]  S. Vasavanonda,et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Lifson,et al.  Energy functions for peptides and proteins. I. Derivation of a consistent force field including the hydrogen bond from amide crystals. , 1974, Journal of the American Chemical Society.

[45]  Xiao He,et al.  A new method for direct calculation of total energy of protein. , 2005, The Journal of chemical physics.

[46]  Ryan P A Bettens,et al.  A new algorithm for molecular fragmentation in quantum chemical calculations. , 2006, The journal of physical chemistry. A.

[47]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[48]  L Wang,et al.  Molecular dynamics and free-energy calculations applied to affinity maturation in antibody 48G7. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[49]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .