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Computational studies to understand molecular regulation of the TRPC6 calcium channel, the mechanism of purine biosynthesis, and the folding of azobenzene oligomers

Tao, Peng
http://rave.ohiolink.edu/etdc/view?acc_num=osu1166718985

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Chemistry.
Different computational chemistry methods were applied to study a variety of problems at the molecular level. These problems are involved with protein-protein interactions, the mechanism of reaction for enzymatic purine biosynthesis, structural interconversion in non-natural oligomeric folding, and carbohydrate synthesis. Molecular dynamic simulations were applied to study the elements of molecular recognition in FKBP12 for binding to transient receptor potential-canonical 6 (TRPC6) calcium channels. A peptide model of the wild-type TRPC6 intracellular domain, a phosphorylated Ser768 analog of the wild-type peptide, and Ser768Asp and Ser768Glu mutants, were subject to FKBP12 binding simulation. The phosphorylated peptide demonstrated the greatest binding affinity, due to the strong interaction between the phosphate group and two lysine (Lys44 and Lys47) residues of FKBP12. The simulations also revealed transient, non-simultaneous interactions with the epsilon-NH3+ group of these lysine residues. Catalytic reaction mechanisms of the enzyme PurE Class I, which catalyzes the transformation from N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) to 4-carboxyaminoimidazole ribonucleotide (CAIR) in the purine biosynthetic pathway, were investigated by density functional theory (DFT) methods. The potential energy surfaces (PES) of these enzymatic reactions have been explored. A cationic pathway is predicted as the most favorable mechanism in both the simplified and full reaction models. Four azobenzene oligomers which could fold into both right- and left-handed helices were studied computationally for their dynamical properties. Two helices were shown as the global minimum among the conformations generated by Monte Carlo simulation. Replica-exchange molecular dynamics (REMD) simulations were performed on these oligomers. Both right- and left-handed helices were successfully sampled in the simulation for all four oligomers. Careful investigation of REMD trajectories revealed twisted conformations as intermediate structures in the interconversion pathway between two helices. Computational studies have been done to understand the mechanism of the regioselective epoxide ring-opening process catalyzed by the presence of (-)-sparteine in the synthesis of beta-arabinofuranosides. MD simulations revealed interesting conformational changes of the (-)-sparteine unit, which could push Li+ toward the epoxide oxygen in a catalytically useful fashion. Quantum molecular dynamics methods were applied to simulate four systems for the epoxide ring-opening process.
Christopher Hadad (Advisor)
499 p.
Chemistry, Physical
Computational Chemistry; Replica Exchange Molecular Dynamics; Density Functional Theory; Monte Carlo; TRPC6; N5-CAIR; Purine Biosynthesis; Azobenzene Foldamers; Sparteine; Arabinofuranosides

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Citations

  • Tao, P. (2007). Computational studies to understand molecular regulation of the TRPC6 calcium channel, the mechanism of purine biosynthesis, and the folding of azobenzene oligomers [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1166718985

    APA Style (7th edition)

  • Tao, Peng. Computational studies to understand molecular regulation of the TRPC6 calcium channel, the mechanism of purine biosynthesis, and the folding of azobenzene oligomers. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1166718985.

    MLA Style (8th edition)

  • Tao, Peng. "Computational studies to understand molecular regulation of the TRPC6 calcium channel, the mechanism of purine biosynthesis, and the folding of azobenzene oligomers." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1166718985

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.