Absolute Binding Free Energy Calculations of Sparsomycin Analogs to the Bacterial Ribosome
The interactions of the 50S subunit of bacterial ribosome with antibiotic sparsomycin (SPS) and five analogs (AN) are investigated through the calculation of the standard (absolute) binding free energy and the characterization of conformational dynamics. The standard binding free energies of the com...
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Veröffentlicht in: | The journal of physical chemistry. B 2010-07, Vol.114 (29), p.9525-9539 |
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description | The interactions of the 50S subunit of bacterial ribosome with antibiotic sparsomycin (SPS) and five analogs (AN) are investigated through the calculation of the standard (absolute) binding free energy and the characterization of conformational dynamics. The standard binding free energies of the complexes are computed using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. Restraining potentials are applied and then released during the simulation to efficiently sample the changes in translational, orientational, and conformational freedom of the ligand and receptor upon binding. The biasing effects of the restraining potentials are rigorously removed. The loss of conformational freedom of the ligand upon binding is determined by introducing a potential of mean force (PMF) as a function of the root-mean-square deviation (rmsd) of the ligand relative to its conformation in the bound state. To reduce the size of the simulated system, the binding pocket of the ribosome is simulated in the framework of the generalized solvent boundary potential (GSBP). The number of solvent molecules in the buried binding site is treated via grand canonical Monte Carlo (GCMC) during the FEP/MD simulations. The correlation coefficient between the calculated and measured binding free energies is 0.96, and the experimentally observed ranking order for the binding affinities of the six ligands is reproduced. However, while the calculated affinities of the strong binders agree well with the experimental values, those for the weak binders are underestimated. |
doi_str_mv | 10.1021/jp100579y |
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The standard binding free energies of the complexes are computed using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. Restraining potentials are applied and then released during the simulation to efficiently sample the changes in translational, orientational, and conformational freedom of the ligand and receptor upon binding. The biasing effects of the restraining potentials are rigorously removed. The loss of conformational freedom of the ligand upon binding is determined by introducing a potential of mean force (PMF) as a function of the root-mean-square deviation (rmsd) of the ligand relative to its conformation in the bound state. To reduce the size of the simulated system, the binding pocket of the ribosome is simulated in the framework of the generalized solvent boundary potential (GSBP). The number of solvent molecules in the buried binding site is treated via grand canonical Monte Carlo (GCMC) during the FEP/MD simulations. The correlation coefficient between the calculated and measured binding free energies is 0.96, and the experimentally observed ranking order for the binding affinities of the six ligands is reproduced. However, while the calculated affinities of the strong binders agree well with the experimental values, those for the weak binders are underestimated.</description><identifier>ISSN: 1520-6106</identifier><identifier>EISSN: 1520-5207</identifier><identifier>DOI: 10.1021/jp100579y</identifier><identifier>PMID: 20608691</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antibiotics, Antineoplastic - chemistry ; B: Statistical Mechanics, Thermodynamics, Medium Effects ; Binding Sites ; Molecular Dynamics Simulation ; Monte Carlo Method ; Ribosome Subunits, Large, Bacterial - chemistry ; Sparsomycin - analogs & derivatives ; Thermodynamics ; Water - chemistry</subject><ispartof>The journal of physical chemistry. 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B</title><addtitle>J. Phys. Chem. B</addtitle><description>The interactions of the 50S subunit of bacterial ribosome with antibiotic sparsomycin (SPS) and five analogs (AN) are investigated through the calculation of the standard (absolute) binding free energy and the characterization of conformational dynamics. The standard binding free energies of the complexes are computed using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. Restraining potentials are applied and then released during the simulation to efficiently sample the changes in translational, orientational, and conformational freedom of the ligand and receptor upon binding. The biasing effects of the restraining potentials are rigorously removed. The loss of conformational freedom of the ligand upon binding is determined by introducing a potential of mean force (PMF) as a function of the root-mean-square deviation (rmsd) of the ligand relative to its conformation in the bound state. To reduce the size of the simulated system, the binding pocket of the ribosome is simulated in the framework of the generalized solvent boundary potential (GSBP). The number of solvent molecules in the buried binding site is treated via grand canonical Monte Carlo (GCMC) during the FEP/MD simulations. The correlation coefficient between the calculated and measured binding free energies is 0.96, and the experimentally observed ranking order for the binding affinities of the six ligands is reproduced. However, while the calculated affinities of the strong binders agree well with the experimental values, those for the weak binders are underestimated.</description><subject>Antibiotics, Antineoplastic - chemistry</subject><subject>B: Statistical Mechanics, Thermodynamics, Medium Effects</subject><subject>Binding Sites</subject><subject>Molecular Dynamics Simulation</subject><subject>Monte Carlo Method</subject><subject>Ribosome Subunits, Large, Bacterial - chemistry</subject><subject>Sparsomycin - analogs & derivatives</subject><subject>Thermodynamics</subject><subject>Water - chemistry</subject><issn>1520-6106</issn><issn>1520-5207</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkD1PwzAQhi0EoqUw8AeQF4QYAraT-GMsVQtIlZD4WFiii-OUVEkc7GTIv8eopRPD6U56n3uHB6FLSu4oYfR-21FCUqHGIzSlKSNRGHG8vzklfILOvN8SwlIm-SmaMMKJ5IpO0ec897YeeoMfqrao2g1eOWPwsjVuM-IF1Hqooa9s67Et8VsHzttm1FWL5y3UduNxb3H_Fd5B98ZVUOPXKrcBMufopITam4v9nqGP1fJ98RStXx6fF_N1BDFN-kiqMuUshjIRShRSQU4SBgmTOedKaM5lCCBOFCVAmIyJLqnIC5LERlMo83iGbna9nbPfg_F91lRem7qG1tjBZyKRSiglZCBvd6R21ntnyqxzVQNuzCjJfk1mB5OBvdq3DnljigP5py4A1zsAtM-2dnDBh_-n6AfrOXmh</recordid><startdate>20100729</startdate><enddate>20100729</enddate><creator>Ge, Xiaoxia</creator><creator>Roux, Benoît</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20100729</creationdate><title>Absolute Binding Free Energy Calculations of Sparsomycin Analogs to the Bacterial Ribosome</title><author>Ge, Xiaoxia ; Roux, Benoît</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-89f5623af4797d89ab042a428b6697c668479a34910a02830cf17bd043ec1afb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Antibiotics, Antineoplastic - chemistry</topic><topic>B: Statistical Mechanics, Thermodynamics, Medium Effects</topic><topic>Binding Sites</topic><topic>Molecular Dynamics Simulation</topic><topic>Monte Carlo Method</topic><topic>Ribosome Subunits, Large, Bacterial - chemistry</topic><topic>Sparsomycin - analogs & derivatives</topic><topic>Thermodynamics</topic><topic>Water - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ge, Xiaoxia</creatorcontrib><creatorcontrib>Roux, Benoît</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of physical chemistry. B</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ge, Xiaoxia</au><au>Roux, Benoît</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Absolute Binding Free Energy Calculations of Sparsomycin Analogs to the Bacterial Ribosome</atitle><jtitle>The journal of physical chemistry. B</jtitle><addtitle>J. Phys. Chem. B</addtitle><date>2010-07-29</date><risdate>2010</risdate><volume>114</volume><issue>29</issue><spage>9525</spage><epage>9539</epage><pages>9525-9539</pages><issn>1520-6106</issn><eissn>1520-5207</eissn><abstract>The interactions of the 50S subunit of bacterial ribosome with antibiotic sparsomycin (SPS) and five analogs (AN) are investigated through the calculation of the standard (absolute) binding free energy and the characterization of conformational dynamics. The standard binding free energies of the complexes are computed using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. Restraining potentials are applied and then released during the simulation to efficiently sample the changes in translational, orientational, and conformational freedom of the ligand and receptor upon binding. The biasing effects of the restraining potentials are rigorously removed. The loss of conformational freedom of the ligand upon binding is determined by introducing a potential of mean force (PMF) as a function of the root-mean-square deviation (rmsd) of the ligand relative to its conformation in the bound state. To reduce the size of the simulated system, the binding pocket of the ribosome is simulated in the framework of the generalized solvent boundary potential (GSBP). The number of solvent molecules in the buried binding site is treated via grand canonical Monte Carlo (GCMC) during the FEP/MD simulations. The correlation coefficient between the calculated and measured binding free energies is 0.96, and the experimentally observed ranking order for the binding affinities of the six ligands is reproduced. However, while the calculated affinities of the strong binders agree well with the experimental values, those for the weak binders are underestimated.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20608691</pmid><doi>10.1021/jp100579y</doi><tpages>15</tpages></addata></record> |
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subjects | Antibiotics, Antineoplastic - chemistry B: Statistical Mechanics, Thermodynamics, Medium Effects Binding Sites Molecular Dynamics Simulation Monte Carlo Method Ribosome Subunits, Large, Bacterial - chemistry Sparsomycin - analogs & derivatives Thermodynamics Water - chemistry |
title | Absolute Binding Free Energy Calculations of Sparsomycin Analogs to the Bacterial Ribosome |
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