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A model binding site for testing scoring functions in molecular docking.
Abstract
Prediction of interaction energies between ligands and their receptors remains a major challenge for structure-based inhibitor discovery. Much effort has been devoted to developing scoring schemes that can successfully rank the affinities of a diverse set of possible ligands to a binding site for which the structure is known. To test these scoring functions, well-characterized experimental systems can be very useful. Here, mutation-created binding sites in T4 lysozyme were used to investigate how the quality of atomic charges and solvation energies affects molecular docking. Atomic charges and solvation energies were calculated for 172,118 molecules in the Available Chemicals Directory using a semi-empirical quantum mechanical approach by the program AMSOL. The database was first screened against the apolar cavity site created by the mutation Leu99Ala (L99A). Compared to the electronegativity-based charges that are widely used, the new charges and desolvation energies improved ranking of known apolar ligands, and better distinguished them from more polar isosteres that are not observed to bind. To investigate whether the new charges had predictive value, the non-polar residue Met102, which forms part of the binding site, was changed to the polar residue glutamine. The structure of the resulting Leu99Ala and Met102Gln double mutant of T4 lysozyme (L99A/M102Q) was determined and the docking calculation was repeated for the new site. Seven representative polar molecules that preferentially docked to the polar versus the apolar binding site were tested experimentally. All seven bind to the polar cavity (L99A/M102Q) but do not detectably bind to the apolar cavity (L99A). Five ligand-bound structures of L99A/M102Q were determined by X-ray crystallography. Docking predictions corresponded to the crystallographic results to within 0.4A RMSD. Improved treatment of partial atomic charges and desolvation energies in database docking appears feasible and leads to better distinction of true ligands. Simple model binding sites, such as L99A and its more polar variants, may find broad use in the development and testing of docking algorithms.
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“In this context, the development of scoring functions adapted for flexible receptor docking is crucial to achieve real improvements in pose and affinity prediction (Totrov and Abagyan, 1997; Wei et al., 2002; Fischer et al., 2014; Ravindranath et al., 2015; Lam et al., 2017; Kong et al., 2018).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Wei et al., 2002
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Cites
A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules
Cornell, W. D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, K. M., Ferguson, D. M., Spellmeyer, D. C., Fox, T., Caldwell, J. W., & Kollman, P. A. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00124a002 · Cited by 13,111
Rapid and efficient site-specific mutagenesis without phenotypic selection.
Kunkel, T. A. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.2.488 · Cited by 7,309
Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen
Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0897 · Cited by 6,763
[19] Rapid and efficient site-specific mutagenesis without phenotypic selection
Kunkel, T. A., Roberts, J. D., & Zakour, R. A. (1987) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(87)54085-x · Cited by 5,191
Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges
Gasteiger, J., & Marsili, M. (1980) · Tetrahedron · doi:10.1016/0040-4020(80)80168-2 · Cited by 4,157
Wang, J., Cieplak, P., & Kollman, P. A. (2000) · Journal of Computational Chemistry · doi:10.1002/1096-987x(200009)21:12 · Cited by 4,048
Rapid measurement of binding constants and heats of binding using a new titration calorimeter
Wiseman, T., Williston, S., Brandts, J. F., & Lin, L. (1989) · Analytical Biochemistry · doi:10.1016/0003-2697(89)90213-3 · Cited by 2,677
Analytical molecular surface calculation
Connolly, M. L. (1983) · Journal of Applied Crystallography · doi:10.1107/s0021889883010985 · Cited by 2,521
A geometric approach to macromolecule-ligand interactions
Kuntz, I. D., Blaney, J. M., Oatley, S. J., Langridge, R., & Ferrin, T. E. (1982) · Journal of Molecular Biology · doi:10.1016/0022-2836(82)90153-x · Cited by 2,287
Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models
Sitkoff, D. F., Sharp, K. A., & Honig, B. H. (1994) · The Journal of Physical Chemistry · doi:10.1021/j100058a043 · Cited by 2,160
Continuum Solvent Studies of the Stability of DNA, RNA, and Phosphoramidate−DNA Helices
Srinivasan, J., Cheatham, T. E., Cieplak, P., Kollman, P. A., & Case, D. A. (1998) · Journal of the American Chemical Society · doi:10.1021/ja981844+ · Cited by 1,634
Nicholls, A. O., & Honig, B. H. (1991) · Journal of Computational Chemistry · doi:10.1002/jcc.540120405 · Cited by 1,270
A new method for predicting binding affinity in computer-aided drug design.
Åqvist, J., Medina, C., & Samuelsson, J. (1994) · Protein Engineering · doi:10.1093/protein/7.3.385 · Cited by 1,043
Qiu, D., Shenkin, P. S., Hollinger, F. P., & Still, W. C. (1997) · The Journal of Physical Chemistry A · doi:10.1021/jp961992r · Cited by 964
Ferrin, T. E., Huang, C. C., Jarvis, L. E., & Langridge, R. (1988) · Journal of Molecular Graphics · doi:10.1016/0263-7855(88)80054-7 · Cited by 950
Automated docking with grid‐based energy evaluation
Meng, E. C., Shoichet, B. K., & Kuntz, I. D. (1992) · Journal of Computational Chemistry · doi:10.1002/jcc.540130412 · Cited by 949
Self-citationAn efficient general-purpose least-squares refinement program for macromolecular structures
Tronrud, D. E., Eyck, L. F. T., & Matthews, B. W. (1987) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767387099124 · Cited by 843
Self-citationÖsterberg, F., Morris, G. M., Sanner, M. F., Olson, A. J., & Goodsell, D. S. (2002) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.10028 · Cited by 474
Simons, K. T., Ruczinski, I., Kooperberg, C. L., Fox, B. A., Bystroff, C., & Baker, D. A. (1999) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19990101)34:1 · Cited by 443
Gómez, J., Hilser, V. J., Xie, D., & Freire, E. (1995) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.340220410 · Cited by 429
Molecular docking using shape descriptors
Shoichet, B. K., Kuntz, I. D., & Bodian, D. L. (1992) · Journal of Computational Chemistry · doi:10.1002/jcc.540130311 · Cited by 429
Self-citationModel for Aqueous Solvation Based on Class IV Atomic Charges and First Solvation Shell Effects
Chambers, C. C., Hawkins, G. D., Cramer, C. J., & Truhlar, D. G. (1996) · The Journal of Physical Chemistry · doi:10.1021/jp9610776 · Cited by 362
Structure-Based Discovery of Inhibitors of Thymidylate Synthase
Shoichet, B. K., Stroud, R. M., Santi, D. V., Kuntz, I. D., & Perry, K. M. (1993) · Science · doi:10.1126/science.8451640 · Cited by 323
Self-citationDiscovery of Small-Molecule Inhibitors of Bcl-2 through Structure-Based Computer Screening
Enyedy, I. J., Ling, Y., Nacro, K., Tomita, Y. A., Wu, X., Cao, Y., Guo, R., Li, B., Zhu, X., Huang, Y. K., et al. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm010016f · Cited by 315
Flexible ligand docking using conformational ensembles
Lorber, D. M., & Shoichet, B. K. (1998) · Protein Science · doi:10.1002/pro.5560070411 · Cited by 294
Self-citationRing, C. S., Sun, E., McKerrow, J. H., Lee, G., Rosenthal, P. J., Kuntz, I. D., & Cohen, F. E. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3583 · Cited by 269
A cavity-containing mutant of T4 lysozyme is stabilized by buried benzene
Sauer-Eriksson, A. E., Baase, W. A., Wozniak, J. A., & Matthews, B. W. (1992) · Nature · doi:10.1038/355371a0 · Cited by 266
Self-citationNew Class IV Charge Model for Extracting Accurate Partial Charges from Wave Functions
Li, J., Zhu, T., Cramer, C. J., & Truhlar, D. G. (1998) · The Journal of Physical Chemistry A · doi:10.1021/jp972682r · Cited by 260
Fast, efficient generation of high-quality atomic charges
Jakalian, A. (2000) · Spectrum Research Repository (Concordia University) · Cited by 254
DesJarlais, R. L., Seibel, G., Kuntz, I. D., Furth, P. S., Alvarez, J. C., de Montellano, P. R. O., DeCamp, D. L., Babé, L. M., & Craik, C. S. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.17.6644 · Cited by 253
Inclusion of Solvation in Ligand Binding Free Energy Calculations Using the Generalized-Born Model
Zou, X., Yaxiong, & Kuntz, I. D. (1999) · Journal of the American Chemical Society · doi:10.1021/ja984102p · Cited by 214
Control of Enzyme Activity by an Engineered Disulfide Bond
Matsumura, M., & Matthews, B. W. (1989) · Science · doi:10.1126/science.2916125 · Cited by 213
Self-citationMorton, A., & Matthews, B. W. (1995) · Biochemistry · doi:10.1021/bi00027a007 · Cited by 194
Self-citationStatistical potentials and scoring functions applied to protein–ligand binding
Gohlke, H., & Klebe, G. (2001) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(00)00195-0 · Cited by 184
Energetic origins of specificity of ligand binding in an interior nonpolar cavity of T4 lysozyme
Morton, A., Baase, W. A., & Matthews, B. W. (1995) · Biochemistry · doi:10.1021/bi00027a006 · Cited by 184
Self-citationA simple method for the calculation of hydration enthalpies of polar molecules with arbitrary shapes
Rashin, A. A., & Namboodiri, K. (1987) · The Journal of Physical Chemistry · doi:10.1021/j100307a038 · Cited by 175
Exhaustive docking of molecular fragments with electrostatic solvation
Majeux, N., Scarsi, M., Apostolakis, J., Ehrhardt, C., & Caflisch, A. (1999) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19991001)37:1 · Cited by 175
Hydration phenomena, classical electrostatics, and the boundary element method
Rashin, A. A. (1990) · The Journal of Physical Chemistry · doi:10.1021/j100368a005 · Cited by 171
Virtual screening with solvation and ligand-induced complementarity
Schnecke, V., & Kuhn, L. A. (2000) · Perspectives in Drug Discovery and Design · doi:10.1023/a:1008737207775 · Cited by 166
A New Ultrasensitive Scanning Calorimeter
Plotnikov, V., Brandts, J. M., Lin, L., & Brandts, J. F. (1997) · Analytical Biochemistry · doi:10.1006/abio.1997.2236 · Cited by 158
The Binding Database: data management and interface design
Chen, X., Lin, Y., Liu, M., & Gilson, M. K. (2002) · Bioinformatics · doi:10.1093/bioinformatics/18.1.130 · Cited by 158
[27] Multiwire area X-ray diffractometers
Hamlin, R. C. (1985) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(85)14029-2 · Cited by 157
Bartolucci, C., Perola, E., Pilger, C., Fels, G., & Lamba, D. (2000) · Proteins Structure Function and Bioinformatics · doi:10.1002/1097-0134(20010201)42:2 · Cited by 151
Ligand−Protein DataBase: Linking Protein−Ligand Complex Structures to Binding Data
Roche, O., Kiyama, R., & Brooks, C. L. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm000467k · Cited by 132
New Linear Interaction Method for Binding Affinity Calculations Using a Continuum Solvent Model
Zhou, R., Friesner, R. A., Ghosh, A., Rizzo, R. C., Jorgensen, W. L., & Levy, R. M. (2001) · The Journal of Physical Chemistry B · doi:10.1021/jp011480z · Cited by 122
The inclusion of electrostatic hydration energies in molecular mechanics calculations
Gilson, M. K., & Honig, B. H. (1991) · Journal of Computer-Aided Molecular Design · doi:10.1007/bf00173467 · Cited by 118
Sippl, W. (2000) · Journal of Computer-Aided Molecular Design · doi:10.1023/a:1008115913787 · Cited by 115
Pang, Y., Perola, E., Xu, K., & Prendergast, F. G. (2001) · Journal of Computational Chemistry · doi:10.1002/jcc.1129 · Cited by 106
Poteete, A. R., Daopin, S., Nicholson, H., & Matthews, B. W. (1991) · Biochemistry · doi:10.1021/bi00219a037 · Cited by 101
Self-citationOn the Probability of Finding a Water Molecule in a Nonpolar Cavity
Wolfenden, R., & Radzicka, A. (1994) · Science · doi:10.1126/science.8052849 · Cited by 91
Improved Scoring of Ligand−Protein Interactions Using OWFEG Free Energy Grids
Pearlman, D. A., & Charifson, P. S. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm000375v · Cited by 89
Inhibitors of Kinesin Activity from Structure-Based Computer Screening
Hopkins, S. C., Vale, R. D., & Kuntz, I. D. (2000) · Biochemistry · doi:10.1021/bi992474k · Cited by 81
Grädler, U., Gerber, H., Goodenough-Lashua, D. M., Garcia, G. A., Ficner, R., Reuter, K., Stubbs, M. T., & Klebe, G. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4256 · Cited by 77
Using CONCORD to construct a large database of three-dimensional coordinates from connection tables
Rusinko, A., Sheridan, R. P., Nilakantan, R., Haraki, K. S., Bauman, N., & Venkataraghavan, R. (1989) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci00064a004 · Cited by 73
Phage T4 lysozyme Physical properties and reversible unfolding
Elwell, M. L., & Schellman, J. A. (1975) · Biochimica et Biophysica Acta (BBA) - Protein Structure · doi:10.1016/0005-2795(75)90273-1 · Cited by 72
The discovery of steroids and other novel FKBP inhibitors using a molecular docking program
Burkhard, P., Hommel, U., Sanner, M. F., & Walkinshaw, M. D. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.2621 · Cited by 65
Knowledge-based interaction potentials for proteins
Rojnuckarin, A., & Subramaniam, S. (1999) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19990701)36:1 · Cited by 59
Collective motion artifacts arising in long-duration molecular dynamics simulations
Chiu, S.-W., Clark, M. M., Subramaniam, S., & Jakobsson, E. (2000) · Journal of Computational Chemistry · doi:10.1002/(sici)1096-987x(20000130)21:2 · Cited by 56
Context‐dependent protein stabilization by methionine‐to‐leucine substitution shown in T4 lysozyme
Lipscomb, L. A., Gassner, N. C., Snow, S. D., Eldridge, A. M., Baase, W. A., Drew, D. L., & Matthews, B. W. (1998) · Protein Science · doi:10.1002/pro.5560070326 · Cited by 53
Self-citationWeiser, J., Weiser, A. A., Shenkin, P. S., & Still, W. C. (1998) · Journal of Computational Chemistry · doi:10.1002/(sici)1096-987x(199805)19:7 · Cited by 52
Use of NMR to Detect Water Within Nonpolar Protein Cavities
Matthews, B. W., Morton, A. G., & Dahlquist, F. W. (1995) · Science · doi:10.1126/science.270.5243.1847 · Cited by 51
Self-citationWray, J. W., Baase, W. A., Lindstrom, J. D., Weaver, L. H., Poteete, A. R., & Matthews, B. W. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3102 · Cited by 49
Self-citationHammarström, L., Liljefors, T., & Gasteiger, J. (1988) · Journal of Computational Chemistry · doi:10.1002/jcc.540090418 · Cited by 42
Modifications of the scoring function in FlexX for virtual screening applications
Ståhl, M. (2000) · Perspectives in Drug Discovery and Design · doi:10.1023/a:1008724921888 · Cited by 29
Kirchhoff, W. H. (1993) · doi:10.6028/nist.tn.1401 · Cited by 29
Park, J. M., No, K. T., Jhon, M. S., & Scheraga, H. A. (1993) · Journal of Computational Chemistry · doi:10.1002/jcc.540141210 · Cited by 28
Liggins, J. R., & Privalov, P. L. (2000) · Proteins Structure Function and Bioinformatics · doi:10.1002/1097-0134(2000)41:4+ · Cited by 24
Modifications of the scoring function in FlexX for virtual screening applications
Ståhl, M. (2005) · Kluwer Academic Publishers eBooks · doi:10.1007/0-306-46883-2_6 · Cited by 15
Research works printed but not linked: 1
- Rarey, 1999, The particle concept: placing discrete water molecules during protein–ligand docking predictions, Proteins: Struct. Funct. Genet., 34, 17, 10.1002/(SICI)1097-0134(19990101)34:1<17::AID-PROT3>3.0.CO;2-1 · DOI
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Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R., Halgren, T. A., Sanschagrin, P. C., & Mainz, D. T. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm051256o · Cited by 7,012
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Metadata
- Authors
- Wei, B. Q., Baase, W. A., Weaver, L. H., Matthews, B. W., & Shoichet, B. K.
- Affiliations
- Northwestern University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Matthews, Brian W.
- Shoichet, Brian K.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2002-09
- Volume
- 322
- Issue
- 2
- Pages
- 339-355
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W1980285986
- Cited by
- 237
- References
- 70
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 9 · 2023: 14 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 16 · 2018: 11 · 2017: 8 · 2016: 13 · 2015: 10 · 2014: 10 · 2013: 9 · 2012: 15
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- National Institutes of Health
- National Institute of General Medical Sciences (GM-21967, GM59957, R01GM059957, R01GM021967)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
- Keywords
- molecular docking, scoring functions, T4 lysozyme, atomic charges, desolvation energy, solvation energy, ligand binding affinity, partial atomic charges, ligand ranking
- MeSH terms
- Algorithms, Binding Sites, Calorimetry, Ligands, Models, Molecular, Muramidase, Mutation, Protein Binding, Protein Conformation, Software, Databases, Factual, Bacteriophage T4, Crystallography, X-Ray, Amino Acid Substitution, Hydrophobic and Hydrophilic Interactions
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