Accurate methods of computing the affinity of a small molecule with a protein are needed to speed the discovery of new medications and biological probes. This paper reviews physics-based models of binding, beginning with a summary of the changes in potential energy, solvation energy, and configurational entropy that influence affinity, and a theoretical overview to frame the discussion of specific computational approaches. Important advances are reported in modeling protein-ligand energetics, such as the incorporation of electronic polarization and the use of quantum mechanical methods. Recent calculations suggest that changes in configurational entropy strongly oppose binding and must be included if accurate affinities are to be obtained. The linear interaction energy (LIE) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods are analyzed, as are free energy pathway methods, which show promise and may be ready for more extensive testing. Ultimately, major improvements in modeling accuracy will likely require advances on multiple fronts, as well as continued validation against experiment.
Calculation of protein-ligand binding affinities. Publishing Authors By Initials
Calculation of protein-ligand binding affinities. Journal Published:
PUBLICATION TYPE: Review
Journal: Annual review of biophysics and biomolecular struc
VOLUME: 36
Page Numbers: 21-42
Journal Abbreviation:
ISSN: 1056-8700
DAY: 3
MONTH: 12
YEAR: 2007
Calculation of protein-ligand binding affinities. Information
Number of References:
LANGUAGE: eng
NlmUniqueID: 9211097
Calculation of protein-ligand binding affinities. Keywords Mesh Terms:
KEYWORDS: Thermodynamics
MESH TERMS: chemistry
Chemical & Substance for Abstract: Calculation of protein-ligand binding affinities. Information
Substance Name: Proteins
Registry Number: 0
Grant and Affiliation Information for Calculation of protein-ligand binding affinities.
AFFILIATION: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850, USA. gilson@umbi.umd.edu
Country: United States
AGENCY: United States NIGMS
GRANT: GM061300
ACRONYM: GM
MEDLINETA: Annu Rev Biophys Biomol Struct
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