We have made significant progress in several areas related to protein dynamics, folding, binding, and function. Structure and dynamics of large multiprotein assemblies. We combined a coarse-grained simulation model and experiments to study the structures and motions of large multiprotein complexes and modular proteins with partially disordered segments. For this we used an ensemble refinement approach that allowed us to combine simulation ensembles and low-resolution x-ray scattering data. In collaboration with the experimental groups of Dr. Hurley and Dr. Eaton (both NIDDK, NIH), we obtained detailed structures of ESCRT-II and of the supercomplex between ESCRT-I and ESCRT-II in solution (1). On the basis of these structures we could propose a detailed model for the function of the ESCRT machinery, which is a major player in membrane protein trafficking and other cellular processes, and is hijacked by viruses, in particular HIV. Dynamic kinase-phosphatase complexes. In collaboration with the groups of Prof. Peti and Prof. Page (Brown University), we used our coarse-grained molecular simulation model to integrate a broad range of experimental data reporting on the structure and dynamics of the complexes formed between MAP kinases and phosphatases. We contributed to the determination of the solution structure of a complete MAPKMAPK-regulatory protein complex, formed between p38alpha and hematopoietic tyrosine phosphatase (HePTP). This structure allowed us to perform a detailed investigation of the molecular basis of specificity and fidelity in MAPK regulation. As part of this collaboration with Profs. Peti and Page, we also determined the structures of MAP kinase ERK2 in complex with HePTP, which is involved in T cell activation in lymphocytes. We found that the resting state of the ERK2:HePTP complex adopts a highly extended, dynamic conformation that becomes compact and ordered in the active state complex. This work demonstrated the significant dynamic structural changes in these complexes, provided the first structural insight into an active state MAPK-phosphatase complex. Computational studies of slow dynamics. We have studied the theoretical foundation and algorithmic realization of string methods to sample slow conformational dynamics (4). We demonstrated that the proper treatment of dynamic effects results in more meaningful transition pathways that capture the reactive flux associated with motion through configuration space. 1. E. Boura, B. Rozycki, H. S. Chung, D. Z. Herrick, B. Canagarajah, D. Cafiso, W. A. Eaton, G. Hummer, J. H. Hurley, Solution structure of the ESCRT-I and -II supercomplex: implications for membrane budding and scission, Structure 20, 874-886 (2012). 2. D. M. Francis, B. Rozycki, D. Koveal, G. Hummer, R. Page, W. Peti, Structural basis of p38αregulation and specificity by hematopoietic tyrosine phosphatase, Nature Chem. Biol. 7, 916-924 (2011). 3. D. M. Francis, B. Rozycki, A Tortajada, G. Hummer, W. Peti, R. Page, Resting and Active States of the ERK2:HePTP Complex, J. Am. Chem. Soc. Communication 133, 1713817141 (2011). 4. M. E. Johnson, G. Hummer, Characterization of a dynamic string method for the construction of transition pathways in molecular reactions, J. Phys. Chem. B 116, 8573-8583 (2012).

Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2012
Total Cost
$730,447
Indirect Cost
City
State
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Johnson, Margaret E; Hummer, Gerhard (2013) Interface-resolved network of protein-protein interactions. PLoS Comput Biol 9:e1003065
Kofinger, Jurgen; Hummer, Gerhard (2013) Atomic-resolution structural information from scattering experiments on macromolecules in solution. Phys Rev E Stat Nonlin Soft Matter Phys 87:052712
Grigoriu, Simina; Bond, Rachel; Cossio, Pilar et al. (2013) The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin. PLoS Biol 11:e1001492
Johnson, Margaret E; Hummer, Gerhard (2013) Evolutionary pressure on the topology of protein interface interaction networks. J Phys Chem B 117:13098-106
Roýýycki, Bartosz; Boura, Evzen; Hurley, James H et al. (2012) Membrane-elasticity model of Coatless vesicle budding induced by ESCRT complexes. PLoS Comput Biol 8:e1002736
Johnson, Margaret E; Hummer, Gerhard (2012) Characterization of a dynamic string method for the construction of transition pathways in molecular reactions. J Phys Chem B 116:8573-83
Boura, Evzen; Ró?ycki, Bartosz; Chung, Hoi Sung et al. (2012) Solution structure of the ESCRT-I and -II supercomplex: implications for membrane budding and scission. Structure 20:874-86
Wikstrom, Marten; Hummer, Gerhard (2012) Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications. Proc Natl Acad Sci U S A 109:4431-6
Waghe, Aparna; Rasaiah, Jayendran C; Hummer, Gerhard (2012) Entropy of single-file water in (6,6) carbon nanotubes. J Chem Phys 137:044709
Mittal, Jeetain; Hummer, Gerhard (2012) Pair diffusion, hydrodynamic interactions, and available volume in dense fluids. J Chem Phys 137:034110

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