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