Role of structural water molecule in HIV protease‐inhibitor complexes: A QM/MM study

Structural water molecule 301 found at the interface of HIV protease‐inhibitor complexes function as a hydrogen bond (H‐bond) donor to carbonyl groups of the inhibitor as well as H‐bond acceptor to amide/amine groups of the flap region of the protease. In this study, six systems of HIV protease‐inhibitor complexes were analyzed, which have the presence of this “conserved” structural water molecule using a two‐layer QM/MM ONIOM method. The combination of QM/MM and QM method enabled the calculation of strain energies of the bound ligands as well as the determination of their binding energies in the ligand–water and ligand–water–protease complexes. Although the ligand experiences considerable strain in the protein bound structure, the H‐bond interactions through the structural water overcomes this strain effect to give a net stability in the range of 16–24 kcal/mol. For instance, in 1HIV system, the strain energy of the ligand was 12.2 kcal/mol, whereas the binding energy associated with the structural water molecule was 20.8 kcal/mol. In most of the cases, the calculated binding energy of structural water molecule showed the same trend as that of the experimental binding free energy values. Further, the classical MD simulations carried out on 1HVL system with and without structural water 301 showed that this conserved water molecule enhances the H‐bond dynamics occurring at the Asp‐bound active site region of the protease‐inhibitor system, and therefore it will have a direct influence on the mechanism of drug action. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008

[1]  Philip M. Dean,et al.  Hydration in drug design. 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions , 1995, J. Comput. Aided Mol. Des..

[2]  John B. O. Mitchell,et al.  Protein Ligand Database (PLD): additional understanding of the nature and specificity of protein-ligand complexes , 2003, Bioinform..

[3]  K. Morokuma,et al.  Is the protein surrounding the active site critical for hydrogen peroxide reduction by selenoprotein glutathione peroxidase? An ONIOM study. , 2006, The journal of physical chemistry. B.

[4]  C. Suresh,et al.  A Base-Sugar-Phosphate Three-Layer ONIOM Model for Cation Binding:  Relative Binding Affinities of Alkali Metal Ions for Phosphate Anion in DNA. , 2007, Journal of chemical theory and computation.

[5]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[6]  U. Singh,et al.  A combined ab initio quantum mechanical and molecular mechanical method for carrying out simulations on complex molecular systems: Applications to the CH3Cl + Cl− exchange reaction and gas phase protonation of polyethers , 1986 .

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

[8]  J. H. Zhang,et al.  Full quantum mechanical study of binding of HIV‐1 protease drugs , 2005 .

[9]  Ad Bax,et al.  NMR Evidence for the Displacement of a Conserved Interior Water Molecule in HIV Protease by a Non-Peptide Cyclic Urea-Based Inhibitor , 1994 .

[10]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[11]  Per E M Siegbahn,et al.  Catalytic mechanism of matrix metalloproteinases: two-layered ONIOM study. , 2002, Inorganic chemistry.

[12]  K. Morokuma,et al.  ONIOM: A Multilayered Integrated MO + MM Method for Geometry Optimizations and Single Point Energy Predictions. A Test for Diels−Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition , 1996 .

[13]  Thom Vreven,et al.  Combining Quantum Mechanics Methods with Molecular Mechanics Methods in ONIOM. , 2006, Journal of chemical theory and computation.

[14]  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 .

[15]  Pietro Cozzini,et al.  Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. , 2004, Journal of medicinal chemistry.

[16]  K. Morokuma,et al.  Effects of the protein environment on the structure and energetics of active sites of metalloenzymes. ONIOM study of methane monooxygenase and ribonucleotide reductase. , 2002, Journal of the American Chemical Society.

[17]  Paul J. Lewi,et al.  Inhibition and substrate recognition – a computational approach applied to HIV protease , 2003, J. Comput. Aided Mol. Des..

[18]  C. Suresh,et al.  Role of Mg2+ and Ca2+ in DNA bending: evidence from an ONIOM-based QM-MM study of a DNA fragment. , 2006, The journal of physical chemistry. A.

[19]  J. B. Molaghan.  Adherence issues in HIV therapeutics. Introduction: the situation. , 1997, The Journal of the Association of Nurses in AIDS Care : JANAC.

[20]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[21]  Philip M. Dean,et al.  Hydration in drug design. 3. Conserved water molecules at the ligand-binding sites of homologous proteins , 1995, J. Comput. Aided Mol. Des..

[22]  Thom Vreven,et al.  Geometry optimization with QM/MM, ONIOM, and other combined methods. I. Microiterations and constraints , 2003, J. Comput. Chem..

[23]  Philip M. Dean,et al.  Hydration in drug design. 2. Influence of local site surface shape on water binding , 1995, J. Comput. Aided Mol. Des..

[24]  J. Gascón,et al.  QM/MM Study of the NMR Spectroscopy of the Retinyl Chromophore in Visual Rhodopsin. , 2005, Journal of chemical theory and computation.

[25]  Johannes C. Hermann,et al.  A combined QM/MM approach to protein--ligand interactions: polarization effects of the HIV-1 protease on selected high affinity inhibitors. , 2004, Journal of medicinal chemistry.

[26]  C. Alsenoy,et al.  Ab initio calculation of the interaction energy in the P2 binding pocket of HIV-1 protease , 2005 .

[27]  Robert G. Parr,et al.  Density Functional Theory of Electronic Structure , 1996 .

[28]  Robert Wieczorek,et al.  The energetic and structural effects of single amino acid substitutions upon capped alpha-helical peptides containing 17 amino acid residues. An ONIOM DFT/AM1 study. , 2005, Journal of the American Chemical Society.