Hostname: page-component-8448b6f56d-qsmjn Total loading time: 0 Render date: 2024-04-25T03:38:41.684Z Has data issue: false hasContentIssue false
  • English
  • Français

Computational Modeling of Solvent Effects on Protein-Ligand Interactions Using Fully Polarizable Continuum Model and Rational Drug Design

Published online by Cambridge University Press:  03 June 2015

Fang Zheng  and
Chang-Guo Zhan
Get access

Abstract

This is a brief review of the computational modeling of protein-ligand interactions using a recently developed fully polarizable continuum model (FPCM) and rational drug design. Computational modeling has become a powerful tool in understanding detailed protein-ligand interactions at molecular level and in rational drug design. To study the binding of a protein with multiple molecular species of a ligand, one must accurately determine both the relative free energies of all of the molecular species in solution and the corresponding microscopic binding free energies for all of the molecular species binding with the protein. In this paper, we aim to provide a brief overview of the recent development in computational modeling of the solvent effects on the detailed protein-ligand interactions involving multiple molecular species of a ligand related to rational drug design. In particular, we first briefly discuss the main challenges in computational modeling of the detailed protein-ligand interactions involving the multiple molecular species and then focus on the FPCM model and its applications. The FPCM method allows accurate determination of the solvent effects in the first-principles quantum mechanism (QM) calculations on molecules in solution. The combined use of the FPCM-based QM calculations and other computational modeling and simulations enables us to accurately account for a protein binding with multiple molecular species of a ligand in solution. Based on the computational modeling of the detailed protein-ligand interactions, possible new drugs may be designed rationally as either small-molecule ligands of the protein or engineered proteins that bind/metabolize the ligand. The computational drug design has successfully led to discovery and development of promising drugs.

Keywords

318287Protein-ligand interactionsolvent effectrational drug designbinding affinity
Type
Research Article
Information
Communications in Computational Physics , Volume 13 , Issue 1 , January 2013 , pp. 31 - 60
Copyright
Copyright © Global Science Press Limited 2013

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

[1]Zhan, C.-G., Norberto de Souza, O., Rittenhouse, R., and Ornstein, R. L., Determination of two structural forms of catalytic bridging ligand in zinc-phosphotriesterase by molecular dynamics simulation and quantum chemical calculation, J. Am. Chem. Soc., 121 (1999), 7279–7282.Google Scholar
[2]Zhan, C.-G. and Zheng, F., First computational evidence for a critical bridging hydroxide ion in phosphodiesterase active site, J. Am. Chem. Soc., 123 (2001), 2835–2838.CrossRefGoogle ScholarPubMed
[3]Koca, J., Zhan, C.-G., Rittenhouse, R., and Ornstein, R. L., Mobility of the active site bound paraoxon and sarin in zinc-phosphotriesterase by molecular dynamics simulation and quantum chemical calculation, J. Am. Chem. Soc., 123 (2001), 817–826.Google Scholar
[4]Zheng, F., Zhan, C.-G., and Ornstein, R. L., Theoretical studies of reaction pathways and energy barriers for base-catalyzed hydrolysis of phosphotriesterase substrates paraoxon and related toxic nerve agents, J. Chem. Soc. Perkin Trans. 2 (2001), 2355–2363.Google Scholar
[5]Xiong, Y., Lu, H., Li, Y., Yang, G., and Zhan, C.-G., Characterization of a catalytic ligand bridging metal ions in phosphodiesterases 4 and 5 by molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations, Biophys. J., 91 (2006), 1858–1867.CrossRefGoogle ScholarPubMed
[6]Xiong, Y., Lu, H.-T., and Zhan, C.-G., Dynamic structures of phosphodiesterase-5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations, J. Comput. Chem., 29 (2008), 1259–1267.Google Scholar
[7]Hamza, A. and Zhan, C.-G., Determination of the structure of human phosphodiesterase-2 in a bound state and its binding with inhibitors by molecular modeling, docking, and dynamics simulation, J. Phys. Chem. B, 113 (2009), 2896–2908.Google Scholar
[8]Wu, S., Xu, D., and Guo, H., QM/MM studies of monozinc β-lactamase CphA suggest that the crystal structure of an enzyme-intermediate complex represents a minor pathway, J. Am. Chem. Soc., 132 (2010), 17986–17988.Google Scholar
[9]Bandyopadhyay, P. and Gordon, M. S., A combined discrete/continuum solvation model: application to glycine, J. Chem. Phys., 113 (2000), 1104–1109.Google Scholar
[10]Warshel, A. and Levitt, M., Theoretical studies of enzymic reactions – dielectric, electrostatic and steric stabilization of carbonium-ion in reaction of lysozyme, J. Mol. Biol., 103 (1976), 227–249.Google Scholar
[11]Field, M. J., Bash, P. A., and Karplus, M., M. A combined quantum-mechanical and molecular mechanical potential for molecular-dynamics simulations, J. Comput. Chem., 11 (1990), 700–733.Google Scholar
[12]Gao, J. and Xia, X., A prior evaluation of aqueous polarization effects through Monte Carlo QM-MM simulation, Science, 258 (1992), 631–635.Google Scholar
[13]Vreven, T. and Morokuma, K., The ONIOM (our own N-layered integrated molecular orbital + molecular mechanics) method for the first singlet excited (S1) state photoisomerization path of a retinal protonated Schiff base, J. Chem. Phys., 113 (2000), 2969–2975.CrossRefGoogle Scholar
[14]Singh, U. and Kollman, P., A combined ab initio quantum-mechanical and molecular mechanical method for carrying out simulations on complex molecular-systems – applications to the CH3O + Cl- exchange-reaction and gas-phase protonation of polyethers, J. Comput. Chem. 7 (1986), 718–730.CrossRefGoogle Scholar
[15]Reuter, N., Dejaegere, A., Maigret, B., and Karplus, M., Frontier bonds in QM/MM methods: A comparison of different approaches, J. Phys. Chem. A, 104 (2000), 1720–1735.Google Scholar
[16]Cui, Q. and Karplus, M., Molecular properties from combined QM/MM methods. I. Analytical second derivative and vibrational calculations, J. Chem. Phys., 112 (2000), 1133–1149.Google Scholar
[17]Cui, Q., Elstner, M., Kaxiras, E., Frauenheim, T., and Karplus, M., A QM/MM implementation of the self-consistent charge density functional tight binding (SCC-DFTB) method, J. Phys. Chem. B, 105 (2001), 569–585.Google Scholar
[18]Trajbl, M., Hong, G. Y., and Warshel, A., Ab initio QM/MM simulation with proper sampling: “First principle” calculations of the free energy of the autodissociation of water in aqueous solution, J. Phys. Chem. B, 106 (2002), 13333–13343.Google Scholar
[19]Rosta, E., Klahn, M., and Warshel, A., Towards accurate ab initio QM/MM calculations of free-energy profiles of enzymatic reactions, J. Phys. Chem. B, 110 (2006), 2934–2941.Google Scholar
[20]Warshel, A., Computer simulations of enzyme catalysis: Methods, progress, and insights, Annual Rev. Biophys. Biomol. Struct. 32(2003), 425–443.Google Scholar
[21]Zhang, Y., Lee, T., and Yang, , A pseudobond approach to combining quantum mechanical and molecular mechanical methods, J. Chem. Phys., 110 (1999), 46–54.Google Scholar
[22]Zhang, Y., Improved pseudobonds for combined ab inito quantum mechanical/molecular mechanical methods, J. Chem. Phys., 122 (2005), 024114.Google Scholar
[23]Liu, H., Zhang, Y., and Yang, W., How is the active site of enolase organized to catalyze two different reaction steps?, J. Am. Chem. Soc., 122 (2000), 6560–6570.CrossRefGoogle Scholar
[24]Zhang, Y., Kua, J., and Mccammon, J., Role of the catalytic triad and oxyanion hole in acetyl-cholinesterase catalysis: An ab initio QM/MM study, J. Am. Chem. Soc., 124 (2002), 10572–10577.Google Scholar
[25]Zhang, Y., Kua, J., and Mccammon, J., Influence of structural fluctuation on enzyme reaction energy barriers in combined quantum mechanical/molecular mechanical studies, J. Phys. Chem. B, 107 (2003), 4459–4463.Google Scholar
[26]Cisneros, G., Liu, H., Zhang, Y., and Yang, W., Ab initio QM/MM study shows there is no general acid in the reaction catalyzed by 4-oxalocrotonate tautornerase, J. Am. Chem. Soc., 125 (2003), 10384–10393.Google Scholar
[27]Cisneros, G., Wang, M., Silinski, P., Fitzgerald, M., and Yang, W., The protein backbone makes important contributions to 4-oxalocrotonate tautomerase enzyme catalysis: Understanding from theory and experiment, Biochemistry, 43 (2004), 6885–6892.CrossRefGoogle ScholarPubMed
[28]Corminboeuf, C., Hu, P., Tuckerman, M. E., and Zhang, Y., Unexpected deacetylation mechanism suggested by a density functional theory QM/MM study of histone-deacetylase-like protein, J. Am. Chem. Soc., 128 (2006), 4530–4531.Google Scholar
[29]Zhang, Y., Liu, H., and Yang, W., Free energy calculations on enzyme reactions with an efficient iterative procedure to determine minimum energy paths on a combined ab initio QM/MM potential, J. Chem. Phys., 112 (2000), 3483–3492.Google Scholar
[30]HuP, P, and Zhang, Y., Catalytic mechanism and product specificity of the histone lysine methyltransferase SET7/9: An ab initio QM/MM-FE study with multiple initial structures, J. Am. Chem. Soc., 128 (2006), 1272–1278.Google Scholar
[31]Liu, J., Hamza, A., and Zhan, C.-G., Fundamental reaction mechanism and free energy profile for (-)-cocaine hydrolysis catalyzed by cocaine esterase, J. Am. Chem. Soc., 131 (2009), 11964–11975.Google Scholar
[32]Liu, J., Zhang, Y., Zhan, C.-G., Fundamental dephosphorylation mechanism of dimethylphosphonyl-inhibited human acetylcholinesterase, J. Phys. Chem. B, 113 (2009), 16226–16236.Google Scholar
[33]Xiong, Y., Liu, J., Yang, G.-F., and Zhan, C.-G., Computational determination of fundamental pathway and free energy barriers for acetohydroxyacid synthase-catalyzed condensation reactions of a-keto acids, J. Comput. Chem., 31 (2010), 1592–1602.Google Scholar
[34]Chen, X., Fang, L., Liu, J., and Zhan, C.-G., Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine, J. Phys. Chem. B, 115 (2011), 1315–1322.Google Scholar
[35]Chen, X., Zhao, X., Xiong, Y., Liu, J., and Zhan, C.-G., Fundamental Reaction Pathway and Free Energy Profile for Hydrolysis of Intracellular Second Messenger Adenosine 3’,5’-Cyclic Monophosphate (cAMP) Catalyzed by Phosphodiesterase-4, J. Phys. Chem. B, 115 (2011), Oct. 5(Epub ahead of print).Google Scholar
[36]Ke, Z., Smith, G. K., Zhang, Y., Guo, H., Molecular mechanism for eliminylation, a newly discovered post-translational modification, J. Am. Chem. Soc., 133 (2011), 11103–11105.Google Scholar
[37]Nicholls, A. and Honig, B., A rapid finite-difference algorithm, utilizing successive overrelaxation to solve the Poisson-Boltzmann equation, J. Comput. Chem. 12(1991), 435–445.Google Scholar
[38]Bashford, D. and Case, D. A., Generalized Bornmodels of Macromolecular Solvation Effects, Annu. Rev. Phys. Chem., 51 (2000), 129–152.Google Scholar
[39]Klamt, A., Conductor-like screening model for real solvents – a new approach to the quantitative calculation of solvation phenomena, J. Phys. Chem., 99 (1995), 2224–2235.Google Scholar
[40]Huang, X., Pan, Y., Zheng, F., and Zhan, C.-G., Reaction pathway and free energy profile for pre-chemical reaction step of human butyrylcholinesterase-catalyzed hydrolysis of (-)- cocaine by combined targeted molecular dynamics and potential of mean force simulations, J. Phys. Chem. B, 114 (2010), 13545–13554.Google Scholar
[41]Huang, X., Zheng, F., and Zhan, C.-G., Human butyrylcholinesterase-cocaine binding pathway and free energy profiles by molecular dynamics and potential of mean force simulations, J. Phys. Chem. B., 115 (2011), 11254–11260.Google Scholar
[42]Rocchia, W., Sridharan, S., Nicholls, A., Alexov, E., Chiabrera, A., and Honig, B., Rapid grid-based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: Applications to the molecular systems and geometric objects, J. Comput. Chem. 23(2002), 128–137.CrossRefGoogle Scholar
[43]Bertonati, C., Honig, B., and Alexov, E., Poisson-Boltzmann calculations of nonspecific salt effects on protein-protein binding free energies. Biophys. J., 92 (2007), 1891–1899.Google Scholar
[44]Zhu, J., Alexov, E., and Honig, B., Comparative study of generalized born models: Born radii and peptide folding, J. Phys. Chem. B., 109 (2005), 3008–3022.Google Scholar
[45]Hamza, A. and Zhan, C.-G., How can (-)-epigallocatechin gallate from green tea prevent HIV-1 virus infection? Mechanistic insights from computational modeling and the implication for rational design of anti-HIV-1 entry inhibitors, J. Phys. Chem. B, 110 (2006), 2910–2917.Google Scholar
[46]Abdul Hameed, M. D. M., Hamza, A., and Zhan, C.-G., Microscopic modes and free energies of 3-phosphoinositide-dependent kinase-1 (PDK1) binding with celecoxib and other inhibitors, J. Phys. Chem. B, 110 (2006), 26365–26374.Google Scholar
[47]Bargagna-Mohan, P., Hamza, A., Kim, Y.-E., Ho, Y. K., Mor-Vaknin, N., Wendschlag, N., Liu, J., Evans, R. M., Markovitz, D. M., Zhan, C.-G., Kim, K. B., and Mohan, R., The tumor inhibitor and anti-angiogenic agent withaferin a targets the intermediate filament protein vimentin, Chemistry & Biology, 14 (2007), 623–634.CrossRefGoogle Scholar
[48]Huang, X. and Zhan, C.-G., How dopamine transporter interacts with dopamine: Insights from molecular modeling and simulation, Biophys. J., 93 (2007), 3627–3639.Google Scholar
[49]Hao, G.-F., Zhu, X.-L., Ji, F.-Q., Yang, G.-F., and Zhan, C.-G., Understanding mechanism of drug resistance due to a codon deletion in protoporphyrinogen oxidase through computational modeling, J. Phys. Chem. B, 113 (2009), 4865–4875.Google Scholar
[50]Zhu, X. L., Hao, G.-F., Zhan, C.-G., and Yang, G.-F., Computational simulations of the interactions between acetyl-coenzyme-A carboxylase and clodinafop: Resistance mechanism due to active and nonactive site mutations, J. Chem. Inf. Modeling, 49 (2009), 1936–1943.Google Scholar
[51]Huang, X., Gu, H., and Zhan, C.-G., Mechanism for cocaine blocking the transport of dopamine: Insights from molecular modeling and dynamics simulations, J. Phys. Chem. B, 113 (2009), 15057–15066.Google Scholar
[52]Zhao, P.-L., Wang, L., Zhu, X.-L., Huang, X., Zhan, C.-G., Wu, J.-W., and Yang, G.-F., Subnanomolar inhibitor of cytochrome bc1 complex designed via optimizing interaction with conformationally flexible residues, J. Am. Chem. Soc., 132 (2010), 185–194.Google Scholar
[53]Hamza, A., Tong, M., Abdul Hameed, M. D. M., Li, H., Goren, A. C., Tai, H.-H., and Zhan, C.-G., Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: Insights from computational alanine scanning and site-directed mutagenesis, J. Phys. Chem. B, 114 (2010), 5605–5616.Google Scholar
[54]Hao, G.-F., Yang, G.-F., and Zhan, C.-G., Computational mutation scanning and drug resistance mechanisms of HIV-1 protease inhibitors, J. Phys. Chem. B, 114 (2010), 9663–9676.Google Scholar
[55]Lei, B., Abdul Hameed, M. D. M., Hamza, A., Wehenkel, M., Muzyka, J. L., Yao, X.-J., Kim, K.-B., and Zhan, C.-G., Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations, J. Phys. Chem. B, 114 (2010), 12333–12339.Google Scholar
[56]Yang, B., Hamza, A., Wang, Y., Chen, G., and Zhan, C.-G., Computational determination of binding structures and free fnergies of phosphodiesterase-2 with benzo[1,4]diazepin-2-one derivatives, J. Phys. Chem. B, 114 (2010), 16020–16028.Google Scholar
[57]Bargagna-Mohan, P., Paranthan, R. R., Hamza, A., Dimova, N., Srinivasan, C., Elliott, G. I., Zhan, C.-G., Lau, D., Cambi, F., and Mohan, R., With aferin A targets intermediate filaments GFAP and vimentin in A model of retinal gliosis, J. Biol. Chem., 285 (2010), 7657–7669.Google Scholar
[58]Fairchild, S. Z., Peterson, M. W., Hamza, A., Zhan, C.-G., Cerasoli, D. M., and Chang, W. E., Computational characterization of how the VX nerve agent binds human serum paraoxonase 1, J. Mol. Model., 17 (2011), 97–109.Google Scholar
[59]Huang, X., Zheng, F., Crooks, P. A., Dwoskin, L. P., Zhan, C.-G., Modeling multiple species of nicotine and deschloroepibatidine interacting with α4β2 nicotinic acetylcholine receptor: From microscopic binding to phenomenological binding affinity, J. Am. Chem. Soc., 127 (2005), 14401–14414.Google Scholar
[60]Huang, X., Zheng, F., Chen, X., Crooks, P. A., Dwoskin, L. P., and Zhan, C.-G., Modeling subtype-selective agonists binding with α4β2 and α7 nicotinic acetylcholine receptors: Effects of local binding and long-range electrostatic interactions, J. Med. Chem., 49 (2006), 7661–7674.Google Scholar
[61]Huang, X., Zheng, F., Stokes, C., Papke, R. L., Zhan, C.-G., Modeling binding modes of α7 nicotinic acetylcholine receptor with ligands: The roles of Gln117 and other residues of the receptor in agonist binding, J. Med. Chem., 51 (2008), 6293–6302.Google Scholar
[62]Rivail, J.-L. and Rinaldi, D., In computational chemistry: Reviews of current trends, Vol. 1; Leszczynski, J. Ed., World Scientific, Singapore, 1996; pp. 139.Google Scholar
[63]Orozco, M. and Luque, F. J., Theoretical methods for the description of the solvent effect in biomolecular systems, Chem. Rev., 100 (2000), 4187–4225.Google Scholar
[64]Tomasi, J., Mennucci, B., and Cammi, R., Quantum mechanical continuum solvation models, Chem. Rev. 105(2005), 2999–3093.Google Scholar
[65]Cramer, C. J. and Truhlar, D. G., A universal approaches to solvation modeling, Acc. Chem. Res., 42 (2009), 493–497.Google Scholar
[66]Clementi, E., Computational Aspects of Large Chemical Systems, Springer, Berlin, 1980.Google Scholar
[67]Florian, J. and Warshel, A., Langevin dipoles model for ab initio calculations of chemical processes in solution: Parametrization and application to hydration free energies of neutral and ionic solutes and conformational analysis in aqueous solution, J. Phys. Chem. B, 101 (1997), 5583–5595.Google Scholar
[68]Broo, A., Pearl, G., and Zerner, M. C., Development of a hybrid quantum chemical and molecular mechanics method with application to solvent effects on the electronic spectra of uracil and uracil derivatives, J. Phys. Chem. A, 101 (1997), 2478–2488.Google Scholar
[69]Jung, Y., Ho Choi, C. H., Gordon, M. S., Adsorption of water on the Si(100) surface: An ab initio and QM/MM cluster study, J. Phys. Chem. B, 105 (2001), 4039–4044.Google Scholar
[70]Hori, T., Takahashi, H., Nakano, M., Nitta, T., and Yang, W., A QM/MM study combined with the theory of energy representation: Solvation free energies for anti/syn acetic acids in aqueous solution, Chem. Phys. Lett., 419 (2006), 240–244.Google Scholar
[71]Acevedo, O. and Jorgensen, W. L., Advances in QM/MM simulations for organic and enzymatic reactions, Acc. Chem. Res., 43 (2010), 142–151.Google Scholar
[72]Tomasi, J. and Persico, M., Molecular interactions in solution: An overview of methods based on continuous distributions of the solvent, Chem. Rev., 94 (1994), 2027–2094.Google Scholar
[73]Cramer, C. J. and Truhlar, D. G., Implicit solvation models: Equilibria, structure, spectra, and dynamics, Chem. Rev., 99 (1999), 2161–2200.Google Scholar
[74]Kinoshita, M. and Hirata, F., Application of the reference interaction site model theory to analysis on surface-induced structure of water, J. Chem. Phys., 104 (1996), 8807–8815.Google Scholar
[75]Palmer, D. S., Sergiievskyi, V. P., Jensen, F., and Fedorov, M. V., Accurate calculations of the hydration free energies of druglike molecules using the reference interaction site model, J. Chem. Phys., 133 (2010), 044104.Google Scholar
[76]Miyata, T., Ikuta, Y., and Hirata, F., Accurate calculations of the hydration free energies of druglike molecules using the reference interaction site model, J. Chem. Phys., 133 (2010), 044114.Google Scholar
[77]Chen, W. and Gordon, M. S., The effective fragment model for solvation: Internal rotation in formamide, J. Chem. Phys., 105 (1996), 11081–11090.Google Scholar
[78]Kerdcharoen, T. and Morokuma, K., ONIOM-XS: An extension of the ONIOM method for molecular simulation in condensed phase, Chem. Phys. Lett., 355 (2002), 257–262.Google Scholar
[79]Kerdcharoen, T. and Morokuma, K., Combined quantum mechanics and molecular mechanics simulation of Ca2+/ammonia solution based on the ONIOM-XS method: Octahedral coordination and implication to biology, J. Chem. Phys., 118 (2003), 8856–8862.Google Scholar
[80]Zhan, C.-G., Landry, D. W., and Ornstein, R. L., Reaction pathways and energy barriers for alkaline hydrolysis of carboxylic acid esters in water studied by a hybrid supermolecule polarizable continuum approach, J. Am. Chem. Soc., 122 (2000), 2621–2627.Google Scholar
[81]Zhan, C.-G. and Dixon, D. A., Absolute hydration free energy of the proton from first-principles electronic structure calculations, J. Phys. Chem. A, 105 (2001), 11534–11540.Google Scholar
[82]Zhan, C.-G. and Dixon, D. A., First-principles determination of absolute hydration free energy of hydroxide ion, J. Phys. Chem. A, 106 (2002), 9737–9744Google Scholar
[83]Zhan, C.-G. and Dixon, D. A., The nature and absolute hydration free energy of the solvated electron in water, J. Phys. Chem. B, 107 (2003), 4403–4417.Google Scholar
[84]Zhan, C.-G. and Dixon, D. A., Hydration of the fluoride anion: Structures and absolute hydration free energy from first-principles electronic structure calculations, J. Phys. Chem. A, 108 (2004), 2020–2029.Google Scholar
[85]Xiong, Y. and Zhan, C.-G., Theoretical studies of the transition state structures and free energy barriers for base-catalyzed hydrolysis of amides, J. Phys. Chem. A, 110 (2006), 12644–12652.Google Scholar
[86]Chipman, D. M., Charge penetration in dielectric models of salvation, J. Chem. Phys., 106 (1997), 10194–10206.Google Scholar
[87]Cossi, M., Barone, V., Cammi, R., and Tomasi, J., Ab initio study of solvated molecules: A new implementation of the polarizable continuum model, Chem. Phys. Lett., 255 (1996), 327–335.Google Scholar
[88]Foresman, J. B., Keith, T. A., Wiberg, K. B., Snoonian, J., and Frisch, M. J., Solvent effects 5. Influence of cavity shape, truncation of electrostatics and electron correlation on ab initio reaction field calculation, J. Phys. Chem., 100 (1996), 16098–16104.Google Scholar
[89]Cances, E., Mennucci, B., and Tomasi, J., A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics, J. Chem. Phys., 107 (1997), 3032–3041.Google Scholar
[90]Tomasi, J., Mennucci, B., and Cances, E., The IEF version of the PCM solvation method: An overview of a new method addressed to study molecular solutes at the QM ab initio level, J. Mol. Struct. (Theochem), 464 (1999), 211–226.Google Scholar
[91]Klamt, A. and Jonas, V., Treatment of the outlying charge in continuum solvation models, J. Chem. Phys., 105 (1996), 9972–9981.Google Scholar
[92]Barone, V. and Cossi, M., Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model, J. Phys. Chem. A, 102 (1998), 1995–2001.Google Scholar
[93]Zhan, C.-G., Bentley, J., and Chipman, D. M., Volume polarization in reaction field theory, J. Chem. Phys. 108(1998), 177–192.Google Scholar
[94]Zhan, C.-G. and Chipman, D. M., Cavity size in reaction field theory, J. Chem. Phys., 109 (1998), 10543.Google Scholar
[95]Zhan, C.-G. and Chipman, D. M., Reaction field effects on nitrogen shielding, J. Chem. Phys., 110(1999), 1611–1622.Google Scholar
[96]Zhan, C.-G., Landry, D. W., and Ornstein, R. L., Energy barriers for alkaline hydrolysis of carboxylic acid esters in aqueous solution by reaction field calculations, J. Phys. Chem. A, 104 (2000), 7672–7678.Google Scholar
[97]Zhan, C.-G. and Landry, D. W., Theoretical studies of competing reaction pathways and energy barriers for alkaline ester hydrolysis of cocaine, J. Phys. Chem. A, 105 (2001), 1296–1301.CrossRefGoogle Scholar
[98]Zhan, C.-G., Niu, S., and Ornstein, R. L., Theoretical studies of fundamental reaction pathways for the three stages of carboxylation of ribulose-1, 5-bisphosphate, J. Chem. Soc. Perkin Trans., 2 (2001), 23–29.Google Scholar
[99]Dixon, D. A., Feller, D., Zhan, C.-G., and Francisco, J. S., Decomposition pathways of peroxynitrous acid: Gas-phase and solution energetics, J. Phys. Chem. A, 106 (2002), 3191–3196.CrossRefGoogle Scholar
[100]Zhan, C.-G., Dixon, D. A., Sabri, M. I., Kim, M.-S., and Spencer, P. S., Theoretical determination of chromophores in the chromogenic effects of neurotoxicants, J. Am. Chem. Soc., 124 (2002), 2744–2752.Google Scholar
[101]Dixon, D. A., Feller, D., Zhan, C.-G., and Francisco, S. F., The gas and solution phase acidities of HNO, HOONO, HONO, and HONO2, Int. J. Mass Spectrom, 227 (2003), 421–438.Google Scholar
[102]Zhan, C.-G., Dixon, D. A., and Spencer, P. S., Computational insights into the chemical structures and mechanisms of the chromogenic and neurotoxic effects of aromatic 7-diketones, J. Phys. Chem. B, 107 (2003), 2853–2861.Google Scholar
[103]Chen, X. and Zhan, C.-G., Fundamental reaction pathways and free energy barriers for ester hydrolysis of intracellular second messenger 3’, 5’-cyclic nucleotide, J. Phys. Chem. A, 108 (2004), 3789–3797.Google Scholar
[104]Chen, X. and Zhan, C.-G., Theoretical determination of activation free energies for alkaline hydrolysis of cyclic and acyclic phosphodiesters in aqueous solution, J. Phys. Chem. A, 108 (2004), 6407–6413.Google Scholar
[105]Zhan, C. G., Spencer, P. S., and Dixon, D. A., Chromogenic and neurotoxic effects of aliphatic γ-diketone: Computational insights into the molecular structures and mechanism, J. Phys. Chem. B, 108 (2004), 6098–6104.Google Scholar
[106]Zhan, C.-G., Deng, S.-X., Skiba, J. G., Hayes, B. A., Tschampel, S. M., and Shields, G. C., and Landry, D. W., First-principle studies of intermolecular and intramolecular catalysis of protonated cocaine, J. Comput. Chem., 26 (2005), 980–986.Google Scholar
[107]Lu, H.-T., Chen, X., and Zhan, C.-G., First-principles calculation of pKa for cocaine, nicotine, neurotransmitters, and anilines in aqueous solution, J. Phys. Chem. B, 111 (2007), 10599–10605.Google Scholar
[108]Chen, X. and Zhan, C.-G., First-principles determination of molecular conformations of cyclic adenosine 3’,5’-monophosphate in gas phase and aqueous solution, J. Phys. Chem. B, 112 (2008), 16851–16859.Google Scholar
[109]Zheng, F., Dwoskin, L. P., Crooks, P. A., and Zhan, C.-G., First-principles determination of molecular conformations of indolizidine (-)-235B’ in solution, Theo. Chem. Acc., 124 (2009), 269–278.Google Scholar
[110]Chipman, D. M., Simulation of volume polarization in reaction field theory, J. Chem. Phys. 110(1999), 8012–8018.Google Scholar
[111]Chipman, D. M., Reaction field treatment of charge penetration, J. Chem. Phys., 112 (2000), 5558–5565.Google Scholar
[112]Chipman, D. M., Comparison of solvent reaction field representations, Theo. Chem. Acta, 107 (2002), 80–89.Google Scholar
[113]Chipman, D. M., Simulation of volume polarization for the influence of solvation on chemical shielding, Theo. Chem. Acta, 111 (2004), 61–65.Google Scholar
[114]Xiong, Y. and Zhan, C.-G., Reaction pathways and free energy barriers for alkaline hydrolysis of insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds: Electrostatic and steric effects, J. Org. Chem., 69 (2004), 8451–8458.Google Scholar
[115]Schmidt, M. W., Baldridge, K. K., Boatz, J. A., Elbert, S. T., Gordon, M. S., Jensen, J. H., Koseki, S., Matsunaga, N., Nguyen, K. A., Su, S. J., Windus, T. L., Dupuis, M., and Montgomery, J. A., General atomic and molecular electronic structure system, J. Comput. Chem., 14 (1993), 1347–1363.Google Scholar
[116]Vilkas, M. J. and Zhan, C.-G., An efficient implementation for determining volume polarization in self-consistent reaction field theory, J. Chem. Phys., 129 (2008), 194109.Google Scholar
[117]Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Montgomery, J. A., Vreven, T., Kudin, K. N., Burant, J. C., Millam, J. M., Iyengar, S. S., Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G. A., Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J. E., Hratchian, H. P., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Ayala, P. Y., Morokuma, K., Voth, G. A., Salvador, P., Dannenberg, J. J., Zakrzewski, V. G., Dapprich, S., Daniels, A. D., Strain, M. C., Farkas, O., Malick, D. K., Rabuck, A. D., Raghavachari, K., Foresman, J. B., Ortiz, J. V., Cui, Q., Baboul, A. G., Clifford, S., Cioslowski, J., Stefanov, B. B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R. L., Fox, D. J., Keith, T., Al-Laham, M. A., Peng, C. Y., Nanayakkara, A., Challacombe, M., Gill, P. M. W., Johnson, B., Chen, W., Wong, M. W., Gonzalez, C., Pople, J. A., Gaussian 03, Revision C.02, Gaussian, Inc., Wallingford CT, 2004.Google Scholar
[118]Cramer, C. J. and Truhlar, D. G., A universal approach to solvation modeling, Acc. Chem. Res., 41 (2008), 760–768.Google Scholar
[119]Liu, J., Kelly, C. P., Goren, A. C., Marenich, A. V., Cramer, C. J., Truhlar, D. G., and Zhan, C.-G., Free energies of solvation with surface, volume, and local electrostatic effects and atomic surface tensions to represent the first solvation shell, J. Chem. Theory Comput., 6 (2010), 1109–1117.Google Scholar
[120]Kelly, C. P., Cramer, C. J., and Truhlar, D. G., SM6: A density functional theory continuum solvation model for calculating aqueous solvation free energies of neutrals, ions, and solute-water clusters, J. Chem. Theory Comput., 1 (2005), 1133–1152.Google Scholar
[121]Li, D., Huang, X., Han, K., and Zhan, C.-G., Catalytic mechanism of cytochrome P450 for 5’-hydroxylation of nicotine: Fundamental reaction pathways and stereoselectivity, J. Am. Chem. Soc. 133(2011), 7416–7427.Google Scholar
[122]Wu, J., Liu, Q., Yu, K., Hu, J., Kuo, Y. P., Seqerberg, M., St. John, P. A., and Lukas, R. J., Roles of nicotinic acetylcholine receptor beta subunits in function of human alpha4-containing nicotinic receptors, J. Physiol., 576 (2006), 103–118.Google Scholar
[123]Karlin, A. and Wilson, G. G., Acetylcholine receptor channelstructure in the resting, open, and desensitized states probed with thesubstituted-cysteine-accessibility method, Proc. Natl. Acad. Sci. U.S.A., 98 (2001), 1241–1248.Google Scholar
[124]Cheng, X., Wang, H., Grant, B., Sine, S. M., and McCammon, J. A., Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors, PLoS Comput. Biol., 2 (2006), 1173–1184.Google Scholar
[125]Huang, X., Zheng, F., and Zhan, C.-G., Modeling differential binding of α4β2 nicotinic acetylcholine receptor with agonists and antagonists, J. Am. Chem. Soc. 130(2008), 16691–16696.Google Scholar
[126]Pan, Y., Gao, D., and Zhan, C.-G., Modeling the catalysis of anticocaine catalytic antibody: Competing reaction pathways and free energy barriers, J. Am. Chem. Soc., 130 (2008), 5140–5149.Google Scholar
[127]Hamza, A., Zhao, X., Tong, M., Tai, H.-H., and Zhan, C.-G., Novel human mPGES-1 inhibitors identified through structure-based virtual screening, Bioorg. Med. Chem., 19 (2011), 6077–6086.Google Scholar
[128]Zhan, C.-G., Zheng, F., and Landry, D. W., Fundamental reaction mechanism for cocaine hydrolysis in human butyrylcholinesterase, J. Am. Chem. Soc., 125 (2003), 2462–2474.Google Scholar
[129]Hamza, A., Cho, H., Tai, H.-H., and Zhan, C.-G., Molecular dynamics simulation of cocaine binding with human butyrylcholinesterase and its mutants, J. Phys. Chem. B, 109(2005), 4776–4782.Google Scholar
[130]Gao, D. and Zhan, C.-G., Modeling effects of oxyanion hole on the ester hydrolysis catalyzed by human cholinesterases, J. Phys. Chem. B, 109 (2005), 23070–23076.Google Scholar
[131]Zhan, C.-G. and Gao, D., Catalytic mechanism and energy barriers for butyrylcholinesterase-catalyzed hydrolysis of cocaine, Biophys. J., 89 (2005), 3863–3872.Google Scholar
[132]Gao, D. and Zhan, C.-G., Modeling evolution of hydrogen bonding and stabilization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase, Proteins, 62 (2006), 99–110.Google Scholar
[133]Pan, Y., Gao, D., Yang, W., Cho, H., Yang, G.-F., Tai, H.-H., and Zhan, C.-G., Computational redesign of human butyrylcholinesterase for anticocaine medication, Proc. Natl. Acad. Sci. USA, 102 (2005), 16656–16661.Google Scholar
[134]Gao, D., Cho, H., Yang, W., Pan, Y., Yang, G.-F., Tai, H.-H., and Zhan, C.-G., Computational design of a human butyrylcholinesterase mutant for accelerating cocaine hydrolysis based on the transition-state simulation, Angew. Chem. Int. Ed., 45 (2006), 653–657.Google Scholar
[135]Pan, Y., Gao, D., Yang, W., Cho, H., and Zhan, C. G., Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants, J. Am. Chem. Soc., 129 (2007), 13537–13543.Google Scholar
[136]Zheng, F., Yang, W., Ko, M.-C., Liu, J., Cho, H., Gao, D., Tong, M., Tai, H.-H., Woods, J. H., and Zhan, C.-G., Most efficient cocaine hydrolase designed by virtual screening of transition states, J. Am. Chem. Soc., 130 (2008), 12148–12155.Google Scholar
[137]Yang, W., Pan, Y., Fang, L., Gao, D., Zheng, F., and Zhan, C.-G., Free energy perturbation simulation on transition states and high-activity mutants of human butyrylcholinesterase for (-)-cocaine hydrolysis, J. Phys. Chem. B, 114 (2010), 10889–10896.Google Scholar
[138]Yang, W., Pan, Y., Zheng, F., Cho, H., Tai, H. H., and Zhan, C.-G., Free-energy perturbation simulation on transition states and redesign of butyrylcholinesterase, Biophys. J., 96 (2009), 1931–1938.Google Scholar
[139]Zheng, F. and Zhan, C.-G., Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose, Org. Biomol. Chem., 6 (2008), 836–843.Google Scholar
[140]Zheng, F. and Zhan, C.-G., Rational design of an enzyme mutant for anticocaine therapeutics, J. Computer-Aided Mol. Design, 22 (2008), 661–671.Google Scholar
[141]Yang, W., Xue, L., Fang, L., and Zhan, C.-G., Characterization of a high-activity mutant of human butyrylcholinesterase against (-)-cocaine, Chemico-Biological Interactions, 187 (2010), 148–152.Google Scholar
[142]Zheng, F., Yang, W., Xue, L., Hou, S., Liu, J., and Zhan, C.-G., Design of high-activity mutants of human butyrylcholinesterase against (-)-cocaine: Structural and energetic factors affecting the catalytic efficiency, Biochemistry, 49 (2010), 9113–9119.Google Scholar
[143]Zheng, F. and Zhan, C.-G., Recent progress in protein drug design and discovery with a focus on novel approaches to the development of anti-cocaine medications, Future Med. Chem. 1 (2009), 515–528.Google Scholar
[144]Zheng, F. and Zhan, C.-G., Enzyme therapy approaches for treatment of drug overdose and addiction, Future Med. Chem., 3 (2011), 9–13.CrossRefGoogle ScholarPubMed
[145]Xue, L., Ko, M.-C., Tong, M., Yang, W., Hou, S., Zheng, F., Woods, J. H., Tai, H. H., and Zhan, C.-G., Rational design, preparation and characterization of high-activity mutants of human butyrylcholinesterase against (-)-cocaine, Mol. Pharmacol., 79 (2011), 290–297.Google Scholar
[146]Teva Pharmaceutical Industries Ltd, BChE Albumin Fusions for the Treatment of Cocaine Abuse, PCT WO 2011/071926 A1 (International Publication Date: June 16, 2011).Google Scholar
[147]Gao, D., Narasimhan, D. L., Macdonald, J., Ko, M.-C., Landry, D. W., Woods, J. H., Sunahara, R. K., and Zhan, C.-G., Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity, Mol. Pharmacol., 75 (2009), 318–323.Google Scholar
[148]Collins, G. T., Brim, R. L., Narasimhan, D., Ko, M.-C., Sunahara, R. K., Zhan, C.-G., and Woods, J. H., Cocaine esterase prevents cocaine-induced toxicity and the ongoing intravenous self-administration of cocaine in rats, J. Pharm. Exp. Ther. 331(2009), 445–455.Google Scholar
[149]Brim, R. L., Nance, M. R., Youngstrom, D. W., Narasimhan, D., Zhan, C.-G., Tesmer, J. J. G., Sunahara, R. K., and Woods, J. H., A thermally stable form of bacterial cocaine esterase: A potential therapeutic agent for treatment of cocaine abuse, Mol. Pharmacol., 77 (2010), 593–600.Google Scholar
[150]Narasimhan, D., Nance, M. R., Gao, D., Ko, M.-C., Macdonald, J., Tamburi, P., Yoon, D., Landry, D. M., Woods, J. H., Zhan, C.-G., Tesmer, J. J. G., and Sunahara, R. K., Structural analysis of thermostabilizing mutations of cocaine esterase, Protein Eng. Des. Sel. 23(2010), 537–547.Google Scholar
[151]Zhan, C.-G., Novel pharmacological approaches to treatment of drug overdose and addiction, Expert Rev. Clinical Pharmacology, 2 (2009), 1–4.Google Scholar