"Molecular Recognition and Docking"

Irwin D. Kuntz
Deptartment of Pharmaceutical Chemistry, University of California, San Francisco

The current status of docking technology and ligand design will be reviewed. While it has been repeatedly possible to identify low micromolar ligands for enzymes and allosteric sites using the Available Chemical Directory (ACD), it requires extensive chemical efforts to move into the low nanomolar range and beyond. Merging combinatorial chemistry strategies with structure-based design principles has greatly enhances the development of libraries of compounds tailored to bind well to targets and to have appropriate selectivity and pharmaceutical properties.

"High-Throughput Docking for Lead Discovery"

Jeffrey M. Blaney
Structural GenomiX, San Diego, CA

We are applying a two-stage approach to docking for lead discovery. The first stage uses fast, conventional docking programs with approximate scoring functions. Mutiple docking programs and multiple scoring functions are applied to several conformations of a single protein target to yield a consensus score for ranking the "best" ligands. The second stage relies on MM/PBSA binding free energy calculations to provide more reliable affinity rankings of the top scoring molecules from docking.

"Using Continuum Solvent Models in Biomolecular Simulations"

David A. Case
Department of Molecular Biology, The Scripps Research Institute

It is often useful in computer simulations to use a simple description of solvation effects, instead of explicitly representing the individual solvent molecules. Continuum dielectric models often work well in describing the thermodynamic aspects of aqueous solvation, and approximations to such models that avoid the need to solve the Poisson equation are attractive because of their computational efficiency. I will discuss on approach, the generalized Born model, which is simple and fast enough to be used for molecular dynamics simulations of proteins and nucleic acids. Strengths and weaknesses will be discussed, both for fidelity to the underlying continuum model, and for the ability to replace explicit consideration of solvent molecules in macromolecular simulations. The focus will be on versions of the generalized Born model that have a pairwise analytical form, and therefore fit most naturally into conventional molecular mechanics calculations.

"TBA"

Bernard R. Brooks
National Institutes of Health

Abstract not yet available. Check back soon.

"Back to Bjerrum: Calculation of Absolute Binding Free Energies"

Kim Sharp
Department of Biochemistry and Biophysics, University of Pennsylvania

The standard theoretical framework for calculating the absolute binding free energy of a macromolecular association reaction A+B->AB characterized by an association constant KAB is to equate chemical potentials of the species on the left and right hand side of this equation, evaluate the chemical potentials and use the relationship DG = -kTln(KAB). This involves (usually hidden) assumptions about what constitutes the bound species, AB, and where the contribution of the solvent appears. We present here an alternative derivation, which can be traced back to Bjerrum, in which the expectation value of the required quantity, KAB, is obtained directly through the usual statistical mechanical expression for evaluating any observable as its ensemble (Boltzmann weighted) average. The generalized Bjerrum approach more clearly delineates: i) The different contributions to binding. ii) The origin of the much discussed and somewhat controversial association entropy term. iii) Where the solvent contribution appears. It also allows the approximations required for practical evaluation of the binding constant in complex macromolecular system, such as implicit solvent potentials and the quasi-harmonic approximation, to be introduced in a well defined way. We provide an example, with application to some test cases that illustrate a range of binding behavior.

"Molecular Modeling of Protein-Ligand Interactions: Detailed Simulations of a Biotin-Streptavidin Complex"

Terry P. Lybrand
Department of Chemistry & Center for Structural Biology, Vanderbilt University

Biotin and streptavidin form the strongest noncovalent complex known in nature, and this complex has become a paradigm for high affinity protein-ligand binding. We have used a combination of ultra-high resolution x-ray crystallography, site-directed mutagenesis, microcalorimetry, and detailed molecular dynamics simulations to determine the basis of this extraordinarily tight binding reaction. Our simulations reproduce quantitatively the thermodynamics data for this complex, and allow us to propose specific roles for selected residues and regions of the streptavidin protein in the ligand binding process. We will present results from recent simulations, along with new experimental data that support the modeling studies.