The long term goal of molecular approaches to biology is to describe living systems in terms of the laws of chemistry and physics. Theoretical methods can serve to complement experimental studies to obtain an understanding of the molecular machines that play a vital role in the function of living cells. The two molecular motors Fi-ATPase and DNA polymerase I (pol I) will be investigated. The rotatory nanomotor, FoFi-ATP synthase, of which Fi-ATPase is the globular catalytic moiety, is responsible for the synthesis of ATP, the energy currency of cells. The model for this motor developed in the previous grant period raises specific questions, which will be investigated. How is the rotation of the y-subunit induced by the conformational changes of the catalytic p-subunits during the ATP hydrolysis cycle? What conformations of the catalytic p-subunits are involved in catalysis? For DNA pol I, the translocation step in DNA replication, which follows incorporation of a new base into the primer strand, will be elucidated. The pathway from the pre-translocation to the post-translocation state will be determined and utilized to obtain the atomic details of the key steps involved. The nature of """"""""short-term memory"""""""" (i.e., the effect of mismatches in the synthesized DNA, away from the active site, on translocation) will be studied. For both motors, classical dynamical methods (in particular, the new restricted perturbation targeted molecular dynamics algorithm) will be used to determine the nature of the pathways and quantum mechanical/molecular simulations will be employed to study the reactions involved. The results will increase our understanding of the diseases caused by malfunction of these motors. Macro-cyclic inhibitors of mitochondrial FoFi-ATPase will be developed as a possible approach to cancer therapy. A knowledge of the mechanism of two molecular motors, FoFi-ATPase, which makes ATP, and DNA polymerase I, which accurately copies DNA, is essential for a description of cellular function. We will study how these motors work and employ the results to find inhibitors for ATP synthesis in the mitochondria, a suggested treatment of cancer, and to interpret the effect of replication errors in DNA synthesis by polymerases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Preusch, Peter C
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Harvard University
Schools of Arts and Sciences
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Zheng, Guishan; Schaefer, Michael; Karplus, Martin (2013) Hemoglobin Bohr effects: atomic origin of the histidine residue contributions. Biochemistry 52:8539-55
Ovchinnikov, Victor; Cecchini, Marco; Karplus, Martin (2013) A simplified confinement method for calculating absolute free energies and free energy and entropy differences. J Phys Chem B 117:750-62
Kalgin, Igor V; Caflisch, Amedeo; Chekmarev, Sergei F et al. (2013) New insights into the folding of a ?-sheet miniprotein in a reduced space of collective hydrogen bond variables: application to a hydrodynamic analysis of the folding flow. J Phys Chem B 117:6092-105
Qi, Yan; Nam, Kwangho; Spong, Marie C et al. (2012) Strandwise translocation of a DNA glycosylase on undamaged DNA. Proc Natl Acad Sci U S A 109:1086-91
Crenshaw, Charisse M; Nam, Kwangho; Oo, Kimberly et al. (2012) Enforced presentation of an extrahelical guanine to the lesion recognition pocket of human 8-oxoguanine glycosylase, hOGG1. J Biol Chem 287:24916-28
Ovchinnikov, Victor; Karplus, Martin (2012) Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin. J Phys Chem B 116:8584-603
Petrella, Robert J (2011) A versatile method for systematic conformational searches: application to CheY. J Comput Chem 32:2369-85
Luo, Guobin; Karplus, Martin (2011) Determining the conformational change that accompanies donor-acceptor distance fluctuations: an umbrella sampling analysis. J Phys Chem B 115:7991-5
Ovchinnikov, Victor; Trout, Bernhardt L; Karplus, Martin (2010) Mechanical coupling in myosin V: a simulation study. J Mol Biol 395:815-33
Qi, Yan; Spong, Marie C; Nam, Kwangho et al. (2010) Entrapment and structure of an extrahelical guanine attempting to enter the active site of a bacterial DNA glycosylase, MutM. J Biol Chem 285:1468-78

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