The Center of Biomedical Research Excellence in Biomolecular Structure and Dynamics at the University of Montana (CBSD COBRE) supports research that applies the methods and concepts of biophysics, structural biology and chemistry to understand the mechanistic basis of biological processes in health and disease. CBSD faculty members are drawn from the basic and biomedical sciences in the Colleges of Humanities and Sciences and the College of Health Professions and Biomedical Sciences. Disciplines represented by Center faculty include cellular biology, pharmacology, neurobiology, biochemistry, synthetic chemistry and computational research in chemistry and biology. The first aim of the Phase II CBSD COBRE program is to support and mentor CBSD Investigators by: a) supporting four Junior Project Investigators who will conduct research in the general theme of small molecules that regulate or mimic protein receptors and enzymes; b) conducting an effective and robust mentoring program to guide Junior Investigators along the path towards academic success and independent funding; c) identifying and supporting strong replacement projects within the CBSD research theme, inviting both established investigators and collaborative projects to strengthen the research cohesion of the Center; and d) maintaining a Pilot Project and Bridge-funding Program to encourage innovative explorative research and sustain productive Investigators while they pursue independent funding. Aim 2 of the proposal is to carry on the work of Phase I to build a strong cohort of CBSD investigators though strategic faculty recruitment, supported by Career Development Awards, emphasizing the structure and dynamics of macromolecular assemblies in biological processes. Aim 3 advances the Core Facility structure of the CBSD by: a) maintaining a strong Administrative Core that provides effective leadership, oversight and financial management of the Center; b) developing additional capability in the Macromolecular X-ray Diffraction Core Facility to conduct protein expression and purification, as well as small molecule X-ray crystallography; c) developing advanced capabilities in the BioSpectroscopy Core Research Laboratory in time-resolved fluorescence spectroscopy, including single molecule analysis, and d) consolidating an integrated collaborative facility for protein modeling and molecular and dynamics in the Molecular Computation Core Facility. Aim 4 of the application is to conduct an array of programmatic activities to promote program cohesion and scientific excellence. An important overall goal of this proposal is to foster a self-sustainable Center by mentoring and supporting a community of outstanding junior and established investigators, and by adopting multiple funding streams to ensure sustainable Core Research Facilities. Project Narrative The Center of Biomolecular Structure and Dynamics, an NIH Center of Biomedical Research Excellence, supports research programs that facilitate the use of biophysical and molecular structural approaches discover new avenues to understand normal and pathological physiological processes. This proposal supports Junior Investigators who are conducting research programs that will lay the groundwork to discover new therapies for diabetes, chronic lung inflammatory disease, and neurodegenerative disease, and that will lay the foundation for new catalytic methods to synthesize pharmaceuticals.