Merging Physical Bioinformatics and Molecular Simulations: Investigating the Function and Docking of HisH/HisF Complexes

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The transient formation of protein complexes and the channeling of ammonia to the active site are major factors in the regulation of histidine biosynthesis. The objective of this project is to investigate the energy landscape of the docking process and the conduction of ammonia through a putative protein channel by integrating methods from molecular dynamics simulations, bioinformatics, and experimental biochemistry. This channel through a globular protein presents a novel scenario not previously studied. The free energy profile of the ammonia transport will be reconstructed from constant velocity steered molecular dynamics trajectories using the Jarzynski identity as well as other statistical mechanical sampling procedures. The overall goal of this research is to understand the mechanism of protein-protein interactions in the formation of large complexes. A bioinformatics approach will be used to suggest pathways for the docking process which can be probed using both steered and interactive molecular dynamics protocols. Merging the techniques of physical bioinformatics and molecular simulations to model this process in a more realistic environment provides an opportunity to understand how these proteins communicate to achieve metabolic regulation. Recently published structures on the transient protein complex of cytochrome c2 to the reaction center of photosynthetic bacteria offer another valuable opportunity to apply the energy landscape analysis to the docking of small redox proteins to integral membrane proteins.Histidine biosynthesis is a model system for studying complex metabolic networks. Regulated production of histidine depends on the complex interplay between nine active sites located on several polypeptide chains. It has been suggested that the formation of protein complexes through protein-protein interactions is a major factor in the regulation of this metabolic pathway. An understanding of how these proteins communicate will have an impact on our understanding of the mechanism of the formation of transient complexes in biological systems. This work will involve a collaboration between experimental biologists and computational biophysicists and the results will be incorporated into the course "Computational Chemical Biology" which is aimed at undergraduates and first-year graduate students interested in research at the interface of chemistry, biology and computer science. The algorithms and approaches to docking developed in this project will be made available to the broader scientific community through a NSF sponsored Summer School on Computational Biophysics and through plugins for the visualization program VMD that is freely distributed. This work is funded jointly by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division.