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40820-B4
A Computational Investigation of Molecular Recognition and Binding Free Energies in Host-Guest Systems

Carol Parish, University of Richmond

Parish Narrative report 48020_B4

 Analyzing Chair and Boat Conformations of Molecules based on Kemp’s Triacid.  In this project we analyzed the conformational preferences of two maleimide substituted cyclohexane derivatives proposed as scaffolds for HIV-1 fusion inhibitors.  Hybrid Low Mode – Monte Carlo (1:1) conformational searches using seven different force fields were performed in combination with the GBSA(water) solvent model.  Low energy structures identified in this way were subjected to geometry optimization on the B3LYP/6-31G** surface.  Results indicate that the 1,3,5-maleimide functionalized 1,3,5-methyl cyclohexane is more stable in the boat conformation while 1,3,5-maleimide functionalized cyclohexane adopts the expected chair conformation with equatorial arms.  None of the force fields studied was able to predict the unexpected preference for the boat conformation of 1,3,5-maleimide functionalized 1,3,5-methyl cyclohexane.  This work was published in the Journal of Computational Chemistry with undergraduate coauthor Sarah Remmert. (“Energetic Analysis of Chair and Boat Conformations of Maleimide Substituted Cyclohexane Derivatives,” Sarah Remmert and Carol Parish, Journal of Computational Chemistry, 2008 in press.)

 Multireference Studies of para-benzyne.  In addition to our conformational work, we have also developed a new project focusing on a multireference quantum characterization of the singlet states of para-benzyne.  We used a state-averaged, multireference complete active space (CAS) for the determination of the vertical excitation energies of valence and Rydberg states of para–benzyne.  Orbitals were generated with a 10- and 32-state averaged multiconfigurational self consistent field (MCSCF) approach.  Electron correlation was included using multireference configuration interaction with singles and doubles (MR-CISD), including Pople correction for size extensivity (MR-CISD+Q), averaged quadratic coupled cluster (MR-AQCC) and MR-AQCC based on linear response theory (MR-AQCC-LRT).  There is a very high density of electronic states in this diradical system – there are more than seventeen states within 7 eV of the ground state including two 3s Rydberg states.  All excitations, except 2¹A_g, are from the p system to the ss* system.  Of the thirty-two states characterized, fifteen were multi-configurational, including the ground ¹A_g state, providing further evidence for the necessity of a multireference approach for p-benzyne.  This work was published in the Journal of Chemical Physics with undergraduate coauthor Evan Wang.  (“An Extended Multireference Study of the Electronic States of para-benzyne,” Evan Wang, Carol Parish and Hans Lischka, Journal of Chemical Physics, 2008 129, 44306:1-44306:8.)

 Push-Pull [14]-pyridoannulenes.  This project was in collaboration with the Russell and Walters groups at the University of Northern Kentucky.  We synthesized and characterized three new isomeric dipyridoannulenes.  These molecules possess differing conjugation pathways between the substituent alkoxy donating groups and the pyridyl acceptor groups. Optical absorption and emission properties of the dipyridoannulenes and their corresponding acyclic precursors were measured and correlated to structural differences, and used to evaluate conjugation effectiveness and charge–transfer pathways.  Optical properties of protonated dipyridoannulenes were also measured and found to be somewhat insensitive to the degree of protonation.  Density functional studies of these systems at the B3LYP/6-31G* level provided insight into the stabilities, polarities and quinoidal character.  An analysis of the HOMO and LUMO molecular orbitals provided further information regarding charge – transfer behavior.  This work was published in the Journal of Organic Chemistry with numerous undergraduate coauthors including Evan Wang and Betsy Nuez from my laboratory.  (“Synthesis, Spectroscopy and Theoretical Calculations for a Series of Push-Pull [14]-pyridoannulenes,” Matthew M. Lauer, James W. Leslie, Ashley Mynar, Shelly A. Stamper, Anthony D. Martinez, Adrian J. Bray, Senai Negassi, Kevin McDonald, Eric Ferraris, Aaron Muzny, Shawn McAvoy, Keith Walters, Keith C. Russell, Evan Wang, Betsy Nuez and Carol Parish, Journal of Organic Chemistry, 2008, 73, 474-484.)

 Ten undergraduate students worked on these and other projects full-time this past summer while fifteen participated during the academic year.  My students were responsible for 22 presentations at regional, national and international meetings.  (7 student poster presentations at the 2007 Southeastern Regional meeting of the American Chemical Society (SETCA), 1 invited student poster at the Beckman symposium at the national ACS meeting in New Orleans, 3 student poster presentations at the 2008 Schrodinger User Group meeting, 2 student talks at the first annual Virginia Tech – Univ of Virginia Theory Summit, 1 student poster at the annual Beckman symposium, 6 student poster presentations at the 2008 MERCURY conference in computational chemistry and 2 invited student talks at the NSF-PIRE symposium at the University of Vienna.)  Six of my students will also be presenting their work at the 2008 Southeastern Regional meeting of the American Chemical Society (SETCA) this coming November.  Five of my seniors have graduated; 1 student is pursuing the D.O. degree at the Philadelphia College of Osteopathic Medicine, 1 student is working as a software engineer at Microsoft and a third student is in a biotechnology graduate program at Georgetown University.  Two other students are working during 08-09 and planning to apply to law school and medical school.

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