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40820-B4
A Computational Investigation of Molecular Recognition and Binding Free Energies in Host-Guest Systems
Parish Narrative report 48020_B4
Bergman Cyclization of Metal-Containing Enediynes. In this project we expand the scope of the Bergman cyclization by exploring computationally the rearrangement of two osmaenediynes and one rhodaenediyne. The three hypothetical metallaenediynes are constructed by substituting the 14-electron Os(PH3)3 fragment for the C, or the 15-electron Os(PH3)3H or Rh(PH3)3 fragments for the sp2 CH fragment of 3-ene-1,5-diyne. This replacement is guided by the isolobal analogy and previous metallabenzene chemistry. The rearrangement of osmaenediyne with an Os(PH3)3 fragment in place of C is exothermic by 3 kcal/mol (the parent Bergman reaction is computed to be endothermic by 5 kcal/mol) and associated with a significant decrease in the barrier to rearrangement, to 13 kcal/mol (the Ea of the parent reaction computed at the same level of theory is 33 kcal/mol). The replacement of a CH by the isolobal analog Os(PH3)3H reduces the energy of activation for the rearrangement to 23 kcal/mol and produces a corresponding metalladiradical that is 8 kcal/mol less stable that the corresponding osmaenediyne. The activation energy corresponding to the rearrangement of the rhodaenediyne is the same as that of the organic parent enediyne. Interesting polytopal rearrangements of metallaenediynes, and the diradical nature of the resulting intermediates are also explored. This work was published in the Journal of the American Chemical Society. (Tuning the Bergman Cyclization by Introduction of Metal Fragments at Various Positions of the Enediyne. MetallaBergman Cyclizations”, Edyta M. Brzostowska, Roald Hoffmann and Carol Parish, Journal of the American Chemical Society, 2007 129, 4401-4409.)
Conformational Analysis of HIV gp41 Cross-Linking Scaffolds. In addition to our enediyne work, we have also developed a new project focusing on the inhibition of HIV fusion. The HIV-1 envelope glycoproteins gp120 and gp41 remain non-covalently associated and oligomerize most likely as trimers on the surface of the virion. This trimeric complex mediates viral entry into target cells, which is initiated by the high affinity interaction between the viral envelope gp120 and the CD4 cellular receptors. The crystal structure of a complex between gp120, CD4 and a neutralizing antibody that blocks the chemokine receptor binding site has been solved showing that this complex has a ternary structure. Modeling studies of the orientation of gp120 in the ternary complex reveal that gp120 is constrained to be three-fold symmetric. A series of trivalent CD4-mimetic miniproteins designed to match the distance between any two of the CD4 binding cavities by having three CD4M9 moieties tethered through a spacer to a three-fold symmetric template have been reported. In this work we examine several new C3 symmetric templates that could serve as scaffolds to which CD-4 mimetic peptides or miniproteins can be attached. Conformational analysis was used to characterize the different rigidities, flexibilities and spatial orientations of each system to better understand their molecular behaviour. Their synthesis and chemical properties as well as the characterization by classical mechanical conformational searching techniques was examined. Mixed Low Mode and Monte Carlo searching techniques were used to exhaustively sample the OPLS2005/GBSA(water) potential energy surface of trisubstituted cyclohexane and benzene derivatives of C3 symmetry. Geometric structure, molecular length, and hydrogen bonding patterns were analyzed. Non-aromatic compounds exhibited exclusively chair conformations at low energies, with a preference for axial or equatorial arms depending upon the presence of additional ring substituent Me groups. Increasing chain length often resulted in overall shorter molecular length, due to additional chain flexibility. These results were consistent with one and two dimensional temperature dependent NMR studies. This work was published in the Journal of Organic Chemistry (Synthesis and Conformational Analysis of Novel Trimeric Maleimide Cross-Linking Reagents”, A. Szczepanska, J. L. Espartero, A. J. Moreno-Vargas, A. T. Carmona, I. Robina, Sarah Remmert and Carol Parish, Journal of Organic Chemistry, 2007 72, 6776-6785.)
Nine undergraduate students worked on these and other projects full-time this past summer while twelve participated during the academic year. Students gained experience by presenting their research findings at the 2007 national meeting of the American Chemical Society in Chicago and at the 2007 MERCURY conference in computational chemistry. They will also be presenting their work at the 2007 Southeastern Regional meeting of the American Chemical Society (SETCA) in October. Of these, only one undergraduate student has graduated; she is currently pursuing the D. Phil in chemistry at Oxford University.
