DOI: 10.3390/ijms13022176. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

10.3390/ijms13022176

Crossref journal-article

MDPI AG

International Journal of Molecular Sciences (1968)

Abstract

Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD) simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors.

Bibliography

Chen, J., Zhang, D., Zhang, Y., & Li, G. (2012). Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations. International Journal of Molecular Sciences, 13(2), 2176â2195.

Authors 4

Jianzhong Chen (first)
Dinglin Zhang (additional)
Yuxin Zhang (additional)
Guohui Li (additional)

References 66 Referenced 23

10.1038/nrm2147 / Nat. Rev. Mol. Cell Biol / p53 in health and disease by Vousden (2007)
10.1016/S1097-2765(03)00529-X / Mol. Cell / Regulation of p53 by Mdm2: Fate Is in the Numbers by Shmueli (2004)
10.1074/jbc.M213034200 / J. Biol. Chem / Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2 by Little (2003)
10.1038/sj.emboj.7601469 / EMBO J / An essential function of the extreme C-terminus of MDM2 can be provided by MDMX by Uldrijan (2006)
10.1073/pnas.0511130103 / Proc. Natl. Acad. Sci. USA / Core domain interactions in full-length p53 in solution by Veprintsev (2006)
10.4161/cc.9.6.10956 / Cell Cycle / Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery by Popowicz (2010)
10.1038/nature05529 / Nature / Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas by Xue (2007)
10.1038/nature05541 / Nature / Restoration of p53 function leads to tumour regression in vivo by Ventura (2007)
10.1016/j.cell.2006.12.007 / Cell / Modeling the therapeutic efficacy of p53 restoration in tumors by Martins (2006)
10.1074/jbc.C600147200 / J. Biol. Chem / MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin by Hu (2006)
10.1016/j.tcb.2010.01.009 / Trends Cell Biol / The p53 orchestra: Mdm2 and Mdmx set the tone by Wade (2010)
10.4161/cc.8.8.8185 / Cell Cycle / High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx by Czarna (2009)
10.1242/jcs.03362 / J. Cell Sci / MDMX: From bench to bedside by Marine (2007)
10.1038/sj.onc.1202281 / Oncogene / Comparative study of the p53-mdm2 and p53-MDMX interfaces by Boettger (1999)
10.1002/bip.20741 / Biopolymers / Targeting protein–protein interactions: Lessons from p53/MDM2 by Murray (2007)
10.1073/pnas.0900947106 / Proc. Natl. Acad. Sci. USA / Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX by Pazgier (2009)
10.1016/j.molmed.2006.11.002 / Trends. Mol. Med / MDM2 inhibitors for cancer therapy by Vassilev (2007)
10.1038/387296a0 / Nature / Mdm2 promotes the rapid degradation of p53 by Haupt (1997)
10.4161/cc.7.8.5754 / Cell Cycle / The pre-clinical development of MDM2 inhibitors in chronic lymphocytic leukemia uncovers a central role for p53 status in sensitivity to Mdm2 inhibitor-mediated apoptosis by Bixby (2008)
10.1002/ddr.20261 / Drug Dev. Res / New developments in small molecules targeting p53 pathways in anticancer therapy by Cheok (2008)
10.1146/annurev.pharmtox.48.113006.094723 / Annu. Rev. Pharmacol. Toxicol / Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy by Shangary (2009)
10.1016/S0014-5793(99)00254-9 / FEBS Lett / MDM2 interacts with MDMX through their RING finger domains by Tanimura (1999)
10.1128/MCB.20.3.1001-1007.2000 / Mol. Cell. Biol / MdmX protects p53 from Mdm2-mediated degradation by Jackson (2000)
10.3390/ijms12010128 / Int. J. Mol. Sci / Insight into a novel p53 single point mutation (G389E) by molecular dynamics simulations by Pirolli (2010)
10.4161/cc.6.19.4740 / Cell Cycle / Molecular basis for the inhibition of p53 by Mdmx by Popowicz (2007)
10.4161/cc.9.6.11067 / Cell Cycle / Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies by Joseph (2010)
10.1016/j.jmb.2010.03.005 / J. Mol. Biol / Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions by Li (2010)
10.1016/j.jmgm.2011.07.003 / J. Mol. Graph. Mod / Molecular modeling and molecular dynamics simulation studies on pyrrolopyrimidine-based [alpha]-helix mimetic as dual inhibitors of MDM2 and MDMX by Lu (2011)
10.1074/jbc.M109.056747 / J. Biol. Chem / Identification and characterization of the first small molecule inhibitor of MDMX by Reed (2010)
10.1021/ci100113p / J. Chem. Inf. Model / Molecular interaction fields and 3D-QSAR studies of p53-MDM2 inhibitors suggest additional features of ligand-target interaction by Dezi (2010)
10.1074/jbc.M109.073056 / J. Biol. Chem / Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX by Phan (2010)
10.1074/jbc.M809096200 / J. Biol. Chem / Crystal structures of human MdmX (HdmX) in complex with p53 peptide analogues reveal surprising conformational changes by Kallen (2009)
10.1007/s10822-010-9366-0 / J. Comput. Aided Mol. Des / A computational analysis of the binding model of MDM2 with inhibitors by Hu (2010)
10.1002/prot.20275 / Proteins / Computational studies and peptidomimetic design for the human p53–MDM2 complex by Zhong (2005)
10.1007/BF00124361 / J. Comput. Aided Mol. Des / Computer-aided drug design: A free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase by Cummins (1993)
10.1002/jcc.20111 / J. Comput. Chem / Prediction of pKa shifts in proteins using a combination of molecular mechanical and continuum solvent calculations by Kuhn (2004)
10.1002/jcc.21268 / J. Comput. Chem / Trypsin ligand binding free energies from explicit and implicit solvent simulations with polarizable potential by Jiao (2009)
10.1021/ja003834q / J. Am. Chem. Soc / Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA by Wang (2001)
10.1006/jmbi.2000.4057 / J. Mol. Biol / Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model1 by Wang (2000)
10.1021/ja003164o / J. Am. Chem. Soc / An analysis of the interactions between the Sem-5 SH3 domain and its ligands using molecular dynamics, free energy calculations, and sequence analysis by Wang (2001)
10.1016/S0006-3495(04)74084-9 / Biophys. J / Revisiting free energy calculations: A theoretical connection to MM/PBSA and direct calculation of the association free energy by Swanson (2004)
10.1021/ja909575j / J. Am. Chem. Soc / Electrostatic polarization makes a substantial contribution to the free energy of avidin-biotin binding by Tong (2010)
10.1016/j.jmgm.2011.06.003 / J. Mol. Graph. Model / Insight into Mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis by Chen (2011)
10.1007/s00894-009-0553-7 / J. Mol. Model / Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: Free energy calculation and molecular dynamic simulation by Chen (2010)
10.1002/chem.200800277 / Chem. Eur. J / Selectivity of neutral/weakly basic P1 group inhibitors of thrombin and trypsin by a molecular dynamics study by Wu (2008)
10.1021/jm0609162 / J. Med. Chem / Molecular dynamics and free energy studies on the wild-type and double mutant HIV-1 protease complexed with amprenavir and two amprenavir-related inhibitors: Mechanism for binding and drug resistance by Hou (2007)
10.1002/prot.21044 / Proteins / A computational analysis of the binding affinities of FKBP12 inhibitors using the MM PB/SA method by Xu (2006)
10.1002/prot.20033 / Proteins / Exploring protein native states and large-scale conformational changes with a modified generalized born model by Onufriev (2004)
10.1021/jp961710n / J. Phys. Chem / Parametrized models of aqueous free energies of solvation based on pairwise descreening of solute atomic charges from a dielectric medium by Hawkins (1996)
10.1021/ct600085e / J. Chem. Theory. Comput / Generalized Born model with a simple, robust molecular volume correction by Mongan (2007)
10.1021/jp066745u / J. Phys.Chem. A / Insights into the strength and origin of halogen bonding: The halobenzene-formaldehyde dimer by Riley (2007)
10.1002/jcc.20788 / J. Comput. Chem / Efficient bond function basis set for interaction energies by Ding (2008)
10.1016/j.jmb.2006.08.007 / J. Mol. Biol / Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114 by Kovalevsky (2006)
10.1021/jm050943c / J. Med. Chem / Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M by Kovalevsky (2006)
Case, D.A., Darden, T.A., Cheatham, T.E., Simmerling, I.C.L., Wang, J., Duke, R.E., Luo, R., Crowley, M., Walker, R.C., and Zhang, W. (2008). AMBER 10, University of California, San Francisco.
Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A., Stratmann, R.E., and Burant, J.C. (1998). Gaussian 98, Gaussian, Inc.
10.1002/jcc.540161106 / J. Comput. Chem / Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins by Cieplak (1995)
10.1002/jcc.20035 / J. Comput. Chem / Development and testing of a general amber force field by Wang (2004)
10.1063/1.445869 / J. Chem. Phys / Comparison of simple potential functions for simulating liquid water by Jorgensen (1983)
10.1007/BF02367312 / Ann. Biomed. Eng / Numerical integration by Coleman (1977)
10.1063/1.464397 / J. Chem. Phys / Particle mesh Ewald: An N log (N) method for Ewald sums in large systems by Darden (1993)
10.1063/1.470117 / J. Chem. Phys / A smooth particle mesh Ewald method by Essmann (1995)
10.1107/S0021889883010985 / J. Appl. Cryst / Analytical molecular surface calculation by Connolly (1983)
10.1371/journal.pone.0010742 / PLoS One / The role of Phe82 and Phe351 in auxin-induced substrate perception by TIR1 ubiquitin ligase: A novel insight from molecular dynamics simulations by Hao (2010)
10.1016/S0022-2836(03)00610-7 / J. Mol. Biol / Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes by Gohlke (2003)
10.1021/ja990935j / J. Am. Chem. Soc / Computational alanine scanning to probe protein-protein interactions: a novel approach to evaluate binding free energies by Massova (1999)

Dates

Type	When
Created	13 years, 6 months ago (Feb. 17, 2012, 11:01 a.m.)
Deposited	1 year, 2 months ago (May 30, 2024, 6:48 p.m.)
Indexed	2 months ago (June 16, 2025, 1:43 a.m.)
Issued	13 years, 6 months ago (Feb. 17, 2012)
Published	13 years, 6 months ago (Feb. 17, 2012)
Published Online	13 years, 6 months ago (Feb. 17, 2012)

Funders 0

None

BibTeX

@article{Chen_2012, title={Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations}, volume={13}, ISSN={1422-0067}, url={http://dx.doi.org/10.3390/ijms13022176}, DOI={10.3390/ijms13022176}, number={2}, journal={International Journal of Molecular Sciences}, publisher={MDPI AG}, author={Chen, Jianzhong and Zhang, Dinglin and Zhang, Yuxin and Li, Guohui}, year={2012}, month=feb, pages={2176–2195} }

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      "article-title": "p53 in health and disease",
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      "author": "Vousden",
      "year": "2007",
      "journal-title": "Nat. Rev. Mol. Cell Biol"
    },
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      "key": "ref_2",
      "doi-asserted-by": "crossref",
      "first-page": "4",
      "DOI": "10.1016/S1097-2765(03)00529-X",
      "article-title": "Regulation of p53 by Mdm2: Fate Is in the Numbers",
      "volume": "13",
      "author": "Shmueli",
      "year": "2004",
      "journal-title": "Mol. Cell"
    },
    {
      "key": "ref_3",
      "doi-asserted-by": "crossref",
      "first-page": "38315",
      "DOI": "10.1074/jbc.M213034200",
      "article-title": "Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2",
      "volume": "278",
      "author": "Little",
      "year": "2003",
      "journal-title": "J. Biol. Chem"
    },
    {
      "key": "ref_4",
      "doi-asserted-by": "crossref",
      "first-page": "102",
      "DOI": "10.1038/sj.emboj.7601469",
      "article-title": "An essential function of the extreme C-terminus of MDM2 can be provided by MDMX",
      "volume": "26",
      "author": "Uldrijan",
      "year": "2006",
      "journal-title": "EMBO J"
    },
    {
      "key": "ref_5",
      "doi-asserted-by": "crossref",
      "first-page": "2115",
      "DOI": "10.1073/pnas.0511130103",
      "article-title": "Core domain interactions in full-length p53 in solution",
      "volume": "103",
      "author": "Veprintsev",
      "year": "2006",
      "journal-title": "Proc. Natl. Acad. Sci. USA"
    },
    {
      "key": "ref_6",
      "doi-asserted-by": "crossref",
      "first-page": "1104",
      "DOI": "10.4161/cc.9.6.10956",
      "article-title": "Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery",
      "volume": "9",
      "author": "Popowicz",
      "year": "2010",
      "journal-title": "Cell Cycle"
    },
    {
      "key": "ref_7",
      "doi-asserted-by": "crossref",
      "first-page": "656",
      "DOI": "10.1038/nature05529",
      "article-title": "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas",
      "volume": "445",
      "author": "Xue",
      "year": "2007",
      "journal-title": "Nature"
    },
    {
      "key": "ref_8",
      "doi-asserted-by": "crossref",
      "first-page": "661",
      "DOI": "10.1038/nature05541",
      "article-title": "Restoration of p53 function leads to tumour regression in vivo",
      "volume": "445",
      "author": "Ventura",
      "year": "2007",
      "journal-title": "Nature"
    },
    {
      "key": "ref_9",
      "doi-asserted-by": "crossref",
      "first-page": "1323",
      "DOI": "10.1016/j.cell.2006.12.007",
      "article-title": "Modeling the therapeutic efficacy of p53 restoration in tumors",
      "volume": "127",
      "author": "Martins",
      "year": "2006",
      "journal-title": "Cell"
    },
    {
      "key": "ref_10",
      "doi-asserted-by": "crossref",
      "first-page": "33030",
      "DOI": "10.1074/jbc.C600147200",
      "article-title": "MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin",
      "volume": "281",
      "author": "Hu",
      "year": "2006",
      "journal-title": "J. Biol. Chem"
    },
    {
      "key": "ref_11",
      "doi-asserted-by": "crossref",
      "first-page": "299",
      "DOI": "10.1016/j.tcb.2010.01.009",
      "article-title": "The p53 orchestra: Mdm2 and Mdmx set the tone",
      "volume": "20",
      "author": "Wade",
      "year": "2010",
      "journal-title": "Trends Cell Biol"
    },
    {
      "key": "ref_12",
      "doi-asserted-by": "crossref",
      "first-page": "1176",
      "DOI": "10.4161/cc.8.8.8185",
      "article-title": "High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx",
      "volume": "8",
      "author": "Czarna",
      "year": "2009",
      "journal-title": "Cell Cycle"
    },
    {
      "key": "ref_13",
      "doi-asserted-by": "crossref",
      "first-page": "371",
      "DOI": "10.1242/jcs.03362",
      "article-title": "MDMX: From bench to bedside",
      "volume": "120",
      "author": "Marine",
      "year": "2007",
      "journal-title": "J. Cell Sci"
    },
    {
      "key": "ref_14",
      "doi-asserted-by": "crossref",
      "first-page": "189",
      "DOI": "10.1038/sj.onc.1202281",
      "article-title": "Comparative study of the p53-mdm2 and p53-MDMX interfaces",
      "volume": "18",
      "author": "Boettger",
      "year": "1999",
      "journal-title": "Oncogene"
    },
    {
      "key": "ref_15",
      "doi-asserted-by": "crossref",
      "first-page": "657",
      "DOI": "10.1002/bip.20741",
      "article-title": "Targeting protein\u2013protein interactions: Lessons from p53/MDM2",
      "volume": "88",
      "author": "Murray",
      "year": "2007",
      "journal-title": "Biopolymers"
    },
    {
      "key": "ref_16",
      "doi-asserted-by": "crossref",
      "first-page": "4665",
      "DOI": "10.1073/pnas.0900947106",
      "article-title": "Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX",
      "volume": "106",
      "author": "Pazgier",
      "year": "2009",
      "journal-title": "Proc. Natl. Acad. Sci. USA"
    },
    {
      "key": "ref_17",
      "doi-asserted-by": "crossref",
      "first-page": "23",
      "DOI": "10.1016/j.molmed.2006.11.002",
      "article-title": "MDM2 inhibitors for cancer therapy",
      "volume": "13",
      "author": "Vassilev",
      "year": "2007",
      "journal-title": "Trends. Mol. Med"
    },
    {
      "key": "ref_18",
      "doi-asserted-by": "crossref",
      "first-page": "296",
      "DOI": "10.1038/387296a0",
      "article-title": "Mdm2 promotes the rapid degradation of p53",
      "volume": "387",
      "author": "Haupt",
      "year": "1997",
      "journal-title": "Nature"
    },
    {
      "key": "ref_19",
      "doi-asserted-by": "crossref",
      "first-page": "971",
      "DOI": "10.4161/cc.7.8.5754",
      "article-title": "The pre-clinical development of MDM2 inhibitors in chronic lymphocytic leukemia uncovers a central role for p53 status in sensitivity to Mdm2 inhibitor-mediated apoptosis",
      "volume": "7",
      "author": "Bixby",
      "year": "2008",
      "journal-title": "Cell Cycle"
    },
    {
      "key": "ref_20",
      "doi-asserted-by": "crossref",
      "first-page": "289",
      "DOI": "10.1002/ddr.20261",
      "article-title": "New developments in small molecules targeting p53 pathways in anticancer therapy",
      "volume": "69",
      "author": "Cheok",
      "year": "2008",
      "journal-title": "Drug Dev. Res"
    },
    {
      "key": "ref_21",
      "doi-asserted-by": "crossref",
      "first-page": "223",
      "DOI": "10.1146/annurev.pharmtox.48.113006.094723",
      "article-title": "Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy",
      "volume": "49",
      "author": "Shangary",
      "year": "2009",
      "journal-title": "Annu. Rev. Pharmacol. Toxicol"
    },
    {
      "key": "ref_22",
      "doi-asserted-by": "crossref",
      "first-page": "5",
      "DOI": "10.1016/S0014-5793(99)00254-9",
      "article-title": "MDM2 interacts with MDMX through their RING finger domains",
      "volume": "447",
      "author": "Tanimura",
      "year": "1999",
      "journal-title": "FEBS Lett"
    },
    {
      "key": "ref_23",
      "doi-asserted-by": "crossref",
      "first-page": "1001",
      "DOI": "10.1128/MCB.20.3.1001-1007.2000",
      "article-title": "MdmX protects p53 from Mdm2-mediated degradation",
      "volume": "20",
      "author": "Jackson",
      "year": "2000",
      "journal-title": "Mol. Cell. Biol"
    },
    {
      "key": "ref_24",
      "doi-asserted-by": "crossref",
      "first-page": "128",
      "DOI": "10.3390/ijms12010128",
      "article-title": "Insight into a novel p53 single point mutation (G389E) by molecular dynamics simulations",
      "volume": "12",
      "author": "Pirolli",
      "year": "2010",
      "journal-title": "Int. J. Mol. Sci"
    },
    {
      "key": "ref_25",
      "doi-asserted-by": "crossref",
      "first-page": "2386",
      "DOI": "10.4161/cc.6.19.4740",
      "article-title": "Molecular basis for the inhibition of p53 by Mdmx",
      "volume": "6",
      "author": "Popowicz",
      "year": "2007",
      "journal-title": "Cell Cycle"
    },
    {
      "key": "ref_26",
      "doi-asserted-by": "crossref",
      "first-page": "1167",
      "DOI": "10.4161/cc.9.6.11067",
      "article-title": "Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies",
      "volume": "9",
      "author": "Joseph",
      "year": "2010",
      "journal-title": "Cell Cycle"
    },
    {
      "key": "ref_27",
      "doi-asserted-by": "crossref",
      "first-page": "200",
      "DOI": "10.1016/j.jmb.2010.03.005",
      "article-title": "Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions",
      "volume": "398",
      "author": "Li",
      "year": "2010",
      "journal-title": "J. Mol. Biol"
    },
    {
      "key": "ref_28",
      "doi-asserted-by": "crossref",
      "first-page": "167",
      "DOI": "10.1016/j.jmgm.2011.07.003",
      "article-title": "Molecular modeling and molecular dynamics simulation studies on pyrrolopyrimidine-based [alpha]-helix mimetic as dual inhibitors of MDM2 and MDMX",
      "volume": "30",
      "author": "Lu",
      "year": "2011",
      "journal-title": "J. Mol. Graph. Mod"
    },
    {
      "key": "ref_29",
      "doi-asserted-by": "crossref",
      "first-page": "10786",
      "DOI": "10.1074/jbc.M109.056747",
      "article-title": "Identification and characterization of the first small molecule inhibitor of MDMX",
      "volume": "285",
      "author": "Reed",
      "year": "2010",
      "journal-title": "J. Biol. Chem"
    },
    {
      "key": "ref_30",
      "doi-asserted-by": "crossref",
      "first-page": "1451",
      "DOI": "10.1021/ci100113p",
      "article-title": "Molecular interaction fields and 3D-QSAR studies of p53-MDM2 inhibitors suggest additional features of ligand-target interaction",
      "volume": "50",
      "author": "Dezi",
      "year": "2010",
      "journal-title": "J. Chem. Inf. Model"
    },
    {
      "key": "ref_31",
      "doi-asserted-by": "crossref",
      "first-page": "2174",
      "DOI": "10.1074/jbc.M109.073056",
      "article-title": "Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX",
      "volume": "285",
      "author": "Phan",
      "year": "2010",
      "journal-title": "J. Biol. Chem"
    },
    {
      "key": "ref_32",
      "doi-asserted-by": "crossref",
      "first-page": "8812",
      "DOI": "10.1074/jbc.M809096200",
      "article-title": "Crystal structures of human MdmX (HdmX) in complex with p53 peptide analogues reveal surprising conformational changes",
      "volume": "284",
      "author": "Kallen",
      "year": "2009",
      "journal-title": "J. Biol. Chem"
    },
    {
      "key": "ref_33",
      "doi-asserted-by": "crossref",
      "first-page": "687",
      "DOI": "10.1007/s10822-010-9366-0",
      "article-title": "A computational analysis of the binding model of MDM2 with inhibitors",
      "volume": "24",
      "author": "Hu",
      "year": "2010",
      "journal-title": "J. Comput. Aided Mol. Des"
    },
    {
      "key": "ref_34",
      "doi-asserted-by": "crossref",
      "first-page": "222",
      "DOI": "10.1002/prot.20275",
      "article-title": "Computational studies and peptidomimetic design for the human p53\u2013MDM2 complex",
      "volume": "58",
      "author": "Zhong",
      "year": "2005",
      "journal-title": "Proteins"
    },
    {
      "key": "ref_35",
      "doi-asserted-by": "crossref",
      "first-page": "535",
      "DOI": "10.1007/BF00124361",
      "article-title": "Computer-aided drug design: A free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase",
      "volume": "7",
      "author": "Cummins",
      "year": "1993",
      "journal-title": "J. Comput. Aided Mol. Des"
    },
    {
      "key": "ref_36",
      "doi-asserted-by": "crossref",
      "first-page": "1865",
      "DOI": "10.1002/jcc.20111",
      "article-title": "Prediction of pKa shifts in proteins using a combination of molecular mechanical and continuum solvent calculations",
      "volume": "25",
      "author": "Kuhn",
      "year": "2004",
      "journal-title": "J. Comput. Chem"
    },
    {
      "key": "ref_37",
      "doi-asserted-by": "crossref",
      "first-page": "1701",
      "DOI": "10.1002/jcc.21268",
      "article-title": "Trypsin ligand binding free energies from explicit and implicit solvent simulations with polarizable potential",
      "volume": "30",
      "author": "Jiao",
      "year": "2009",
      "journal-title": "J. Comput. Chem"
    },
    {
      "key": "ref_38",
      "doi-asserted-by": "crossref",
      "first-page": "5221",
      "DOI": "10.1021/ja003834q",
      "article-title": "Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA",
      "volume": "123",
      "author": "Wang",
      "year": "2001",
      "journal-title": "J. Am. Chem. Soc"
    },
    {
      "key": "ref_39",
      "doi-asserted-by": "crossref",
      "first-page": "567",
      "DOI": "10.1006/jmbi.2000.4057",
      "article-title": "Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model1",
      "volume": "303",
      "author": "Wang",
      "year": "2000",
      "journal-title": "J. Mol. Biol"
    },
    {
      "key": "ref_40",
      "doi-asserted-by": "crossref",
      "first-page": "3986",
      "DOI": "10.1021/ja003164o",
      "article-title": "An analysis of the interactions between the Sem-5 SH3 domain and its ligands using molecular dynamics, free energy calculations, and sequence analysis",
      "volume": "123",
      "author": "Wang",
      "year": "2001",
      "journal-title": "J. Am. Chem. Soc"
    },
    {
      "key": "ref_41",
      "doi-asserted-by": "crossref",
      "first-page": "67",
      "DOI": "10.1016/S0006-3495(04)74084-9",
      "article-title": "Revisiting free energy calculations: A theoretical connection to MM/PBSA and direct calculation of the association free energy",
      "volume": "86",
      "author": "Swanson",
      "year": "2004",
      "journal-title": "Biophys. J"
    },
    {
      "key": "ref_42",
      "doi-asserted-by": "crossref",
      "first-page": "5137",
      "DOI": "10.1021/ja909575j",
      "article-title": "Electrostatic polarization makes a substantial contribution to the free energy of avidin-biotin binding",
      "volume": "132",
      "author": "Tong",
      "year": "2010",
      "journal-title": "J. Am. Chem. Soc"
    },
    {
      "key": "ref_43",
      "doi-asserted-by": "crossref",
      "first-page": "46",
      "DOI": "10.1016/j.jmgm.2011.06.003",
      "article-title": "Insight into Mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis",
      "volume": "30",
      "author": "Chen",
      "year": "2011",
      "journal-title": "J. Mol. Graph. Model"
    },
    {
      "key": "ref_44",
      "doi-asserted-by": "crossref",
      "first-page": "459",
      "DOI": "10.1007/s00894-009-0553-7",
      "article-title": "Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: Free energy calculation and molecular dynamic simulation",
      "volume": "16",
      "author": "Chen",
      "year": "2010",
      "journal-title": "J. Mol. Model"
    },
    {
      "key": "ref_45",
      "doi-asserted-by": "crossref",
      "first-page": "8704",
      "DOI": "10.1002/chem.200800277",
      "article-title": "Selectivity of neutral/weakly basic P1 group inhibitors of thrombin and trypsin by a molecular dynamics study",
      "volume": "14",
      "author": "Wu",
      "year": "2008",
      "journal-title": "Chem. Eur. J"
    },
    {
      "key": "ref_46",
      "doi-asserted-by": "crossref",
      "first-page": "1177",
      "DOI": "10.1021/jm0609162",
      "article-title": "Molecular dynamics and free energy studies on the wild-type and double mutant HIV-1 protease complexed with amprenavir and two amprenavir-related inhibitors: Mechanism for binding and drug resistance",
      "volume": "50",
      "author": "Hou",
      "year": "2007",
      "journal-title": "J. Med. Chem"
    },
    {
      "key": "ref_47",
      "doi-asserted-by": "crossref",
      "first-page": "1058",
      "DOI": "10.1002/prot.21044",
      "article-title": "A computational analysis of the binding affinities of FKBP12 inhibitors using the MM PB/SA method",
      "volume": "64",
      "author": "Xu",
      "year": "2006",
      "journal-title": "Proteins"
    },
    {
      "key": "ref_48",
      "doi-asserted-by": "crossref",
      "first-page": "383",
      "DOI": "10.1002/prot.20033",
      "article-title": "Exploring protein native states and large-scale conformational changes with a modified generalized born model",
      "volume": "55",
      "author": "Onufriev",
      "year": "2004",
      "journal-title": "Proteins"
    },
    {
      "key": "ref_49",
      "doi-asserted-by": "crossref",
      "first-page": "19824",
      "DOI": "10.1021/jp961710n",
      "article-title": "Parametrized models of aqueous free energies of solvation based on pairwise descreening of solute atomic charges from a dielectric medium",
      "volume": "100",
      "author": "Hawkins",
      "year": "1996",
      "journal-title": "J. Phys. Chem"
    },
    {
      "key": "ref_50",
      "doi-asserted-by": "crossref",
      "first-page": "156",
      "DOI": "10.1021/ct600085e",
      "article-title": "Generalized Born model with a simple, robust molecular volume correction",
      "volume": "3",
      "author": "Mongan",
      "year": "2007",
      "journal-title": "J. Chem. Theory. Comput"
    },
    {
      "key": "ref_51",
      "doi-asserted-by": "crossref",
      "first-page": "1688",
      "DOI": "10.1021/jp066745u",
      "article-title": "Insights into the strength and origin of halogen bonding: The halobenzene-formaldehyde dimer",
      "volume": "111",
      "author": "Riley",
      "year": "2007",
      "journal-title": "J. Phys.Chem. A"
    },
    {
      "key": "ref_52",
      "doi-asserted-by": "crossref",
      "first-page": "275",
      "DOI": "10.1002/jcc.20788",
      "article-title": "Efficient bond function basis set for interaction energies",
      "volume": "29",
      "author": "Ding",
      "year": "2008",
      "journal-title": "J. Comput. Chem"
    },
    {
      "key": "ref_53",
      "doi-asserted-by": "crossref",
      "first-page": "161",
      "DOI": "10.1016/j.jmb.2006.08.007",
      "article-title": "Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114",
      "volume": "363",
      "author": "Kovalevsky",
      "year": "2006",
      "journal-title": "J. Mol. Biol"
    },
    {
      "key": "ref_54",
      "doi-asserted-by": "crossref",
      "first-page": "1379",
      "DOI": "10.1021/jm050943c",
      "article-title": "Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M",
      "volume": "49",
      "author": "Kovalevsky",
      "year": "2006",
      "journal-title": "J. Med. Chem"
    },
    {
      "key": "ref_55",
      "unstructured": "Case, D.A., Darden, T.A., Cheatham, T.E., Simmerling, I.C.L., Wang, J., Duke, R.E., Luo, R., Crowley, M., Walker, R.C., and Zhang, W. (2008). AMBER 10, University of California, San Francisco."
    },
    {
      "key": "ref_56",
      "unstructured": "Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A., Stratmann, R.E., and Burant, J.C. (1998). Gaussian 98, Gaussian, Inc."
    },
    {
      "key": "ref_57",
      "doi-asserted-by": "crossref",
      "first-page": "1357",
      "DOI": "10.1002/jcc.540161106",
      "article-title": "Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins",
      "volume": "16",
      "author": "Cieplak",
      "year": "1995",
      "journal-title": "J. Comput. Chem"
    },
    {
      "key": "ref_58",
      "doi-asserted-by": "crossref",
      "first-page": "1157",
      "DOI": "10.1002/jcc.20035",
      "article-title": "Development and testing of a general amber force field",
      "volume": "25",
      "author": "Wang",
      "year": "2004",
      "journal-title": "J. Comput. Chem"
    },
    {
      "key": "ref_59",
      "doi-asserted-by": "crossref",
      "first-page": "926",
      "DOI": "10.1063/1.445869",
      "article-title": "Comparison of simple potential functions for simulating liquid water",
      "volume": "79",
      "author": "Jorgensen",
      "year": "1983",
      "journal-title": "J. Chem. Phys"
    },
    {
      "key": "ref_60",
      "doi-asserted-by": "crossref",
      "first-page": "322",
      "DOI": "10.1007/BF02367312",
      "article-title": "Numerical integration",
      "volume": "5",
      "author": "Coleman",
      "year": "1977",
      "journal-title": "Ann. Biomed. Eng"
    },
    {
      "key": "ref_61",
      "doi-asserted-by": "crossref",
      "first-page": "10089",
      "DOI": "10.1063/1.464397",
      "article-title": "Particle mesh Ewald: An N log (N) method for Ewald sums in large systems",
      "volume": "98",
      "author": "Darden",
      "year": "1993",
      "journal-title": "J. Chem. Phys"
    },
    {
      "key": "ref_62",
      "doi-asserted-by": "crossref",
      "first-page": "8577",
      "DOI": "10.1063/1.470117",
      "article-title": "A smooth particle mesh Ewald method",
      "volume": "103",
      "author": "Essmann",
      "year": "1995",
      "journal-title": "J. Chem. Phys"
    },
    {
      "key": "ref_63",
      "doi-asserted-by": "crossref",
      "first-page": "548",
      "DOI": "10.1107/S0021889883010985",
      "article-title": "Analytical molecular surface calculation",
      "volume": "16",
      "author": "Connolly",
      "year": "1983",
      "journal-title": "J. Appl. Cryst"
    },
    {
      "key": "ref_64",
      "doi-asserted-by": "crossref",
      "first-page": "e10742",
      "DOI": "10.1371/journal.pone.0010742",
      "article-title": "The role of Phe82 and Phe351 in auxin-induced substrate perception by TIR1 ubiquitin ligase: A novel insight from molecular dynamics simulations",
      "volume": "5",
      "author": "Hao",
      "year": "2010",
      "journal-title": "PLoS One"
    },
    {
      "key": "ref_65",
      "doi-asserted-by": "crossref",
      "first-page": "891",
      "DOI": "10.1016/S0022-2836(03)00610-7",
      "article-title": "Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes",
      "volume": "330",
      "author": "Gohlke",
      "year": "2003",
      "journal-title": "J. Mol. Biol"
    },
    {
      "key": "ref_66",
      "doi-asserted-by": "crossref",
      "first-page": "8133",
      "DOI": "10.1021/ja990935j",
      "article-title": "Computational alanine scanning to probe protein-protein interactions: a novel approach to evaluate binding free energies",
      "volume": "121",
      "author": "Massova",
      "year": "1999",
      "journal-title": "J. Am. Chem. Soc"
    }
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