Tami Marrone

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Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as 'soft' and 'hard' failures. While a soft failure arises when the search algorithm(More)
Studying the thermodynamics of biochemical association reactions at the microscopic level requires efficient sampling of the configurations of the reactants and solvent as a function of the reaction pathways. In most cases, the associating ligand and receptor have complementary interlocking shapes. Upon association, loosely connected or disconnected solvent(More)
Structure-based computational methods continue to enhance progress in the discovery and refinement of therapeutic agents. Several such methods and their applications are described. These include molecular visualization and molecular modeling, docking, fragment methods, 3-D database techniques, and free-energy perturbation. Related issues that are discussed(More)
The catalytic domains of protein kinases are commonly treated as independent modular units with distinct biological functions. Here, the interactions between the catalytic and juxtamembrane domains of VEGFR2 are studied. Highly purified preparations of the receptor tyrosine kinase VEGFR2 catalytic domain without (VEGFR2-CD) and with (VEGFR2-CD/JM) the(More)
We examine the water solvation of the complex of the inhibitors DMP323 and A76928 bound to HIV-1 protease through grand canonical Monte Carlo simulations, and demonstrate the ability of this method to reproduce crystal waters and effectively predict water positions not seen in the DMP323 or A76928 structures. The simulation method is useful for identifying(More)
Computer methods are used extensively in the design and refinement of drug leads. A short summary is given for several computational methods followed by a description of how some of these methods have been applied to design drugs targeted to the renin-angiotensin system and to cholinergic synapses. These methods include quantitative structure-activity(More)
Molecular dynamics and free energy simulations were performed to examine the binding of (8R)-deoxycoformycin and (8R)-coformycin to adenosine deaminase. The two inhibitors differ only at the 2' position of the sugar ring; the sugar moiety of conformycin is ribose, while it is deoxyribose for deoxycoformycin. The 100 ps molecular dynamics trajectories reveal(More)
The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships(More)
Computer simulations using the simplified energy function and simulated tempering dynamics have accurately determined the native structure of the pYVPML, SVLpYTAVQPNE, and SPGEpYVNIEF peptides in the complexes with SH2 domains. Structural and equilibrium aspects of the peptide binding with SH2 domains have been studied by generating temperature-dependent(More)
Structure and energetics of the Src Src Homology 2 (SH2) domain binding with the recognition phosphopeptide pYEEI and its mutants are studied by a hierarchical computational approach. The proposed structure prediction strategy includes equilibrium sampling of the peptide conformational space by simulated tempering dynamics with the simplified,(More)