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Overview
Our work
focuses on the application of theory, computer models, and informatics to noncovalent
binding and molecular recognition. We are particularly interested in
developing software and data resources that will be of value in
understanding these phenomena and in designing molecules that bind to
specific targets. See our publications for
more information on the material below.
The support of the NIH's National Institute of General
Medical Sciences is gratefully acknowledged.
Research Highlights
Theory
- Theoretical formulation for computing the free energy of binding that
accounts correctly for standard concentration.
- "Double decoupling" method of computing binding free energies via thermodynamic
integration or free energy perturbation.
- Theory justifying use of an implicit solvation model in binding calculations.
- Correction of MINTA's neglect of Jacobian determinant.
- Theory for calculating affinities of weak-binding complexes, with proposed
definition of the "bound complex".
- Development of an entropy expansion that approximates the entropy of a
molecule in terms of singlet, doublet, and higher-order correlation terms.
Methods
- Conformational search algorithm suitable for macrocycles and
host-guest complexes.
- Calculation of molecular configurational integrals by summing
over energy minima. First generation method only sampled torsion
angles. second generation method (M2) samples all degrees of freedom
and can be used for macrocycles and complexes.
- Docking algorithm and software.
- Demonstration that homology models of proteins can be used for
compound screening by docking.
- Fast algorithm for finding symmetries of molecules and complexes.
- Rapid assignment of high-quality partial charges to drug-like compounds.
Applications and Insights
- Explanation of affinity trends in a series of HIV protease inhibitors.
- Identification of proflavine as an inhibitor of inhibitor of RRE binding to Rev.
- Accurate calculation of host-guest affinities: synthetic adenine
and barbiturate receptors; molecular clips and tweezers;
cyclodextrin-drug complexes.
- Discovery that host-guest binding is accompanied by large losses
in configurational entropy.
- Evidence that physics-based docking energies overestimate free
energies because they neglect large losses in configurational entropy.
Informatics
- BindingDB, web-accessible database of measured binding affinities.
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