Terry P. Lybrand
In our laboratory, we utilize computational methods to study the properties and behavior of biomacromolecules and ligand-biomacromolecule complexes, and to aid in the design of small molecule ligands with desired binding properties for targeted receptors. Techniques used include quantum mechanical calculations, molecular dynamics and Monte Carlo simulation, and free energy perturbation methods. Computational methods complement experimental techniques and can enhance our understanding of biomacromolecular function.
Our current research interests are focused in several key areas. One area of research involves the use of computational methods to provide detailed molecular models for ligand-macromolecule recognition and binding processes. These studies can also suggest structural modifications for ligands (or biomacromolecules) that may enhance desired biological effects. For example, one active research project uses molecular modeling tools to help explain the molecular basis for the exquisitely tight binding of biotin to streptavidin. Collaborators are using site-directed mutagenesis, calorimetry, and x-ray crystallography to provide supporting data in these studies. Another project focuses on detailed study of cyclooxygenase structure-function relationships, reaction mechanism details, and inhibitor complexes.
A second area of research employs molecular modeling techniques, together with data from biochemical and biophysical studies, to generate three-dimensional models for proteins and protein-ligand complexes not currently tractable to direct experimental structural characterization. Most effort at present focuses on generation of 3D models for integral membrane receptor proteins that function in signal transduction pathways. One project involves an examination of structure-function relationships in bacterial chemotaxis receptors.
A final area of major research activity involves the development
of new mathematical models and computer software to aid in
modeling studies such as those outlined above. Much effort in recent
years involves the development of methods to calculate free energy
differences and solvation effects accurately in molecular dynamics
simulations, as well as the development of algorithms for analysis
and graphical display of simulation results.
K.E. Furse, D.A. Pratt, N.A. Porter, and T.P. Lybrand "Molecular dynamics simulations of arachidonic acid complexes with COX-1 and COX-2: Insights into equilibrium behavior" Biochemistry 45:3189-3205 (2006)
D.S. Cerutti, I. Le Trong, R.E. Stenkamp, and T.P. Lybrand "Simulations of a protein crystal: Explicit treatment of crystallization conditions links theory and experiment in the streptavidin:biotin complex" Biochemistry 47:12065-12077 (2008)
D.S. Cerutti, R.E. Duke, T.A. Darden, and T.P. Lybrand "Staggered Mesh Ewald: An Extension of the Smooth Particle-Mesh Ewald Method Adding Great Versatility" J. Chem. Theory Comput. 5:2322-2338 (2009)
L. Baugh, I. Le Trong, D.S. Cerutti, S. Gülich, P.S. Stayton, R.E. Stenkamp, and T.P. Lybrand "A Distal Point Mutation in the Streptavidin-Biotin Complex Preserves Structure but Diminishes Binding Affinity: Experimental Evidence for Electronic Polarization Effects?" Biochemistry 49:4568-4570 (2010)
I. Le Trong, Z. Wang, D.E. Hyre, T.P. Lybrand, P.S. Stayton, and R.E. Stenkamp "Streptavidin and its Biotin Complex at Atomic Resolution" Acta Cryst. D67:813-821 (2011)
L. Baugh, I. Le Trong, D.S. Cerutti, N. Mehta, S. Gülich, P.S. Stayton, R.E. Stenkamp, and T.P. Lybrand “Second contact shell mutation diminishes streptavidin-biotin binding affinity through transmitted effects on equilibrium dynamics” Biochemistry 51:597-607 (2012)
I. Le Trong, V. Chu, Y. Xing, T.P. Lybrand, P.S. Stayton, and R.E. Stenkamp "Structural consequences of cutting a binding loop: Two circularly permutted variants of streptavidin" Acta Cryst. D69:968-977 (2013)
J.A. Smith, S.J. Edwards, C.W. Moth, and T.P. Lybrand "TagDock:
An efficient rigid body docking algorithm for oligomeric protein
complex model construction and experiment planning"
Biochemistry 52:5577-5584 (2013)