Simulating Protein Structures, Complexes, And Dynamics

Computer Research And Technology

Investigators

Linked publications & trials

Abstract

We have continued to develop, implement, and apply simulation methods in computational studies of the energetics and dynamics of biomolecular systems. We are working to refine a continuum description of macromolecular solvation in terms of polar, nonpolar, and solvent-structure effects. One manuscript has been published (J Phys Chem B, 2007), and another is in preparation.[unreadable] [unreadable] We also model proteins based on homology and work to improve the generation and refinement of such models. With NICHD, we have been studying the inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes, and a manuscript has been submitted. Collaborating with OD, we modeled a deletion mutant of the HIV envelope glycoprotein gp120 for which exposure of the CD4 binding site leads to enhanced binding of two monoclonal antibodies. A manuscript was submitted for this study.[unreadable] [unreadable] In collaboration with NIMH and NHLBI, we are about to submit a manuscript describing reliable ways of determining the transition state of peripheral benzodiazepine receptor ligands that are utilized as probes for brain imaging. With NIDA, we are studying the structure-activity relationships of opioid-receptor ligands. One paper has been published (J Med Chem, 2007), and another is nearly competed. [unreadable] [unreadable] Ongoing collaborative research with NCI includes the design and synthesis of a new series of HSP90 inhibitors. [unreadable] [unreadable] With NICHD, we are studying the dynamics and energetics of AANAT, the first enzyme in the serotonin-melatonin conversion pathway. Also with NICHD, we have been using Monte Carlo and molecular dynamics simulations to study the structural nature of prolactin-receptor interactions and the specificity of binding and recognition. Prolactin is a hormone that has been implicated in the development of human breast tumors.[unreadable] [unreadable] We have also been working to develop computational methods for obtaining reliable structures of G protein coupled receptors (GPCRs). Realistic models could be used to investigate the interactions of GPCRs with extracellular and intracellular signaling molecules.