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 protein-ligand complexes and protein oligomer assemblies not currently tractable to direct experimental structural characterization. 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 analyze correlated
structural fluctuations and solvation effects accurately in molecular dynamics
simulations, as well as the development of algorithms for analysis
and graphical display of simulation results.
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)
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)
NOTE: The TagDock sofware toolkit can be downloaded here:
S.M. Stow, C.R. Goodwin, M. Kliman, B.O. Bachmann, J.A. McLean and T.P. Lybrand "Distance geometry protocol to generate conformations of natural products to structurally interpret ion mobility-mass spectrometry collision cross sections" J. Phys. Chem. B 118:13812-13820 (2014)
D.K. Weber, S. Yao, N. Rojko, G. Anderluh, T.P. Lybrand, M.T. Downton, J. Wagner and F. Separovic "Characterization of the lipid-binding site of equinatoxin II by NMR and molecular dynamcics simulation" Biophys. J. 108:1987-1996 (2015)
M.E. Konkle, A.L. Blobaum, C.W. Moth, J.J. Prusakiewicz, S. Xu, K. Ghebreselasie, D. Akingbade, A.T. Jacobs, C.A. Rouzer, T.P. Lybrand and L.J. Marnett "Conservative secondary shell substitution in Cyclooxygenase-2 reduces inhibition by indomethacin amides and esters via altered enzyme dynamics" Biochemistry 55:348-359 (2016)
M.-B. Sárosi, W. Neumann, T.P. Lybrand and E. Hey-Hawkins "Molecular modeling of the interactions between carborane-containing analogs of indomethacin and cyclooxygenase-2" J. Chem. Inf. Model. 57:2056-2067 (2017)
M.-B. Sárosi and T.P. Lybrand "Molecular dynamics simulation of cyclooxygenase-2 complexes with indomethacin close- carborane analogs" J. Chem. Inf. Model. 58:1990-1999 (2018)
M. Egli and T.P. Lybrand "Enhanced dispersion and polarization
interactions achieved through dithiophosphate group incorporation
yield a dramatic binding affinity increase for an RNA aptamer-
J. Am. Chem. Soc. 141:4445-4452 (2019)