Vanderbilt Biomolecular Modeling Symposium

Poster Session/Competition

The participant judged to have the best poster will receive a $250 prize for their effort. We only have space for about 20 to 25 posters so be sure to sign up early! To sign up, select the poster session checkbox on the registration page and enter your title and abstract in the text box.

Poster Exhibition Guidelines: Each exhibitor will be given a 60" wide x 40" tall space on which to mount their poster with push pins. Your poster should fit within this space and be readable from a distance of ~3 feet.

Be sure to check this space for updates. We will display new poster titles and abstracts here as we receive them.

Poster Titles and Abstracts

1. "Synthesis of Novel Inhibitors of Rhamnose Biosynthesis; discovery through virtual screening of an in silico combinatorial library."

Kerim Babaoglu
Structural Biology Department, University of Tennessee

Virtual screening has recently been demonstrated to be a successful approach to discovering novel compounds with activities against a variety of targets. It has become a viable alternative/parallel approach to high-throughput random library screening. In this study, a virtual combinatorial library of 3519 molecules based on a 4-thiazolidinone core was created using CombiLibmaker®. The library was then docked, using FlexX™ into the target enzyme from Mycobacteria tuberculosis : dTDP-6-deoxy-L-xylo-4-hexulose reductase (RmlC). RmlC is a key step in the essential rhamanose synthetic pathway of M.tuberculosis and represents a promising drug target as humans do not rquire rhamnose and have no RmlC homolog. The docked solutions were ranked using the CSCORE™ consensus scoring funtion. The top 5% of the docked, scored solutions were slated for synthesis. Out of this small percentage of the total library we have identified compounds with inhibitory activity against both the target enzyme as well as activity against whole cell Mycobateria.

---

2. "Molecular Dynamics studies of a capsular polysaccharide from N. meningitidis"

Maral Basma
Complex Carbohydrate Research Center, University of Georgia

Group B Neisseria meningitidis is one of the major pathogens responsible for meningitis infections. The group B meningicoccal polysaccharide consists of an alpha (2 -> 6) linked homopolymer of sialic acid residues. Elucidation of the conformational behavior of the group B polysaccharide is essential for understanding its immunological properties and developing an effective vaccine for the meningitis infections. In this study, molecular dynamics (MD) simulations were carried out in explicit solvent, on a decassaccharide fragment of the homopolymer. The results of the MD simulations were compared to the experimental NMR data from literature.

---

3. "Computational and Experimental Approaches to Combating Antibiotic Resistance."

Ricky Cox
Department of Chemistry, Murray State University

The rise in bacterial resistance to antibiotics has reached a crisis level and is considered a public health emergency. Pathogenic bacteria have countered the overuse of antibiotics by expressing a multitude of gene products that render the drugs ineffective. A family of bacterial enzymes that serves as detoxifying agents of aminoglycoside antibiotics has been identified as aminoglycoside 3´ -phosphotransferases (APH(3´)). Studies on a specific enzyme, APH(3´)-IIIa, have revealed a pi-stacking interaction between Tyr-42 of the enzyme and the adenine ring of a bound nucleotide. The presence of the pi-stacking interaction has provided a basis for exploiting this important contact for inhibitor design and the testing of various nucleosides that can stack with Tyr-42 and block the nucleotide-binding site of APH(3´)-IIIa. Enzyme kinetic studies on various nucleosides and nucleoside-type molecules with APH(3´)-IIIa have established which type of aromatic systems can block the active site of the enzyme. Computational methods were also utilized to map and explore the electrostatic environment of APH(3´)-IIIa and to rationalize the kinetic studies on a variety of potential inhibitors. Overall, experimental and computational studies have revealed a strict electrostatic requirement for inhibitors that target the nucleotide-binding site of APH(3´)-IIIa and enabled the development of a molecular template for inhibitor design strategies. This research is a significant step toward the design of APH-type enzyme inhibitors and has implications in combating antibiotic resistance.

---

4. "Application of NRS technique in the selection and analysis of a Discrete Markov Model for the Human Heart Sodium channel."

Azida Hosein-Sooklal
Department of Physics, Tulane University

Ion channels are protein macromolecules within cell membranes. Extensive studies on these ion channels have resulted in the development of kinetic models that describe the possible transitions of the molecule as it changes from a closed state (C) to an open state (O). Standard techniques involve the use of electrophysiological data obtained from stepped potentials and there have been many different kinetic models proposed for the same ion channel. Rather than using steady stepped potential protocols, Nonequilibrium Response Spectroscopy (NRS), the technique of using rapidly fluctuating voltage pulses in the study of ion channels is applied to a study aimed at distinguishing among competing models for the human heart sodium channel and to analyze the selected model. NRS have been known to drive an ensemble of ion channels far from equilibrium, where it has been argued that new details of the channel kinetics can be studied under nonequilibrium conditions. Single complex waves are designed to produce different responses from the models using wavelets. Experimental results are obtained from whole cell patch-clamp recordings. Comparison of the continuous wavelet transform of the experimental data and the model response shows the better of the two models. The selected model is then further investigated using two types of NRS pulses. Single complex pulses that were cutom-built to maximize parameter sensitivity and ensemble pulses in the form of dichotomous noise. Data obtained from whole cell patch-clamp experiments are used to produce dispersion plots of the model parameters obtained from parameter search algorithms. These plots show how interesting and new information of the different transitional states within the channel can be obtained.

---

5. "The Role of Solvent in Determining Carbohydrate Conformation"

Karl Kirschner
Complex Carbohydrate Research Center, University of Georgia

The relationship between the three-dimensional structures of oligosaccharides and their biological properties has been the focus of many recent studies. The overall conformation and topology of a glycan depends primarily on the orientations of the constituent glycosidic torsion angles (phi, psi, and omega). Experimental studies of glucopyranosides have shown that the omega torsion angle prefers the gauche conformation, which is in contrast to predictions based on gas-phase quantum calculations. In contrast, the omega angle in galactopyranosides displays a preference for the anti conformation. Although it is generally recognized that the gauche effect in carbohydrates arises from interactions with the solvent, the mechanism through which the solvent induces the gauche preference is not understood. In the present work, quantum mechanics, molecular mechanics, and molecular dynamics calculations were performed on representative carbohydrates to determine the origin of the preferred conformations of the omega angle. We show that correct reproduction of the experimental omega angle was obtained after explicit water was included in the MD simulations. The primary role of the water appears to be to disrupt the intramolecular hydrogen bonds of the carbohydrates, thereby allowing the internal electronic and steric repulsions to determine the carbohydrate conformation. This explanation provides a deeper understanding of the behavior of (1->6) linked carbohydrates than was previously available.

---

6. "Molecular recognition trends in two-component signal transduction: insights into the role of a-helix 1 in the OmpR subfamily of response regulators using comparative modeling"

Douglas Kojetin
Department of Molecular and Structural Biochemistry, North Carolina State University

The evolutionarily conserved architecture of two-component signal transduction modules, found in both eukaryotic and prokaryotic systems, provides a simple way for the host to sense external and internal stimuli. It also raises questions as to the degree of similarity and how these signaling proteins recognize and activate their respective partners. To gain further insight into general response regulator:kinase recognition mechanisms, a comparative modeling study of receiver domains from the OmpR subfamily of response regulators in both Escherichia coli (15 members) and Bacillus subtilis (15 members) was performed. These results suggest that a-helix 1 on the receiver domain may be important for kinase recognition. This region displays hydrophobic and electrostatic variability that likely contributes to recognition specificity. Other regions such as the b4-a4 loop and a-helix 5 display less hydrophobic variability, but could also contribute to molecular recognition. Trends in the hydrophobic and electrostatic surfaces of these receiver domains reveal areas of potential biological and structural importance involved in recognition.

---

7. "The State of Art in Theoretical Chemistry"

Preston MacDougall
Department of Chemistry, Middle Tennessee State University

EVolVis is a synthesis of recent advances in quantum chemistry and state-of-the-art computer graphics techniques. A brief description of the algorithm, and selected renderings of biomolecules will be presented. In addition to being beautiful, the images contain new information that is both physically and chemically significant.

---

8. "Rotamer populations from MD simulations and quantum-calculated J-couplings"

Jorge Gonzalez Outeirino
Complex Carbohydrate Research Center, University of Georgia

It is well established that three bond J-couplings are related to the torsion angles between the coupled spins, and empirical Karplus-type equations have been used to quantify this relationship. Numerous parameterizations for these equations have been reported for different spin systems, based on curve fitting to experimental and theoretical 3J-values. It is thus possible to estimate the conformation of a torsion angle from experimental 3J-coupling constants, as well as determine the population of conformations for a bond rotation process. Unfortunately, such empirical approaches are generally insensitive to atomic environment and secondary electronic effects like hyperconjugation. A consequence of these limitations is the prediction of small or negative rotamer populations, which have no physical meaning. These limitations may be removed by computing the J-values quantum mechanically. However, to do this it is necessary to select a representative conformation for the quantum calculations. To minimize the subjective nature of this selection process, we propose to select representative rotamers (rotational isomeric states (RIS)) from unrestrained MD simulations. The RIS model has the further advantage over gas-phase models, in that the RIS conformational states are those present in solution (as determined by solvated MD simulations). Quantum J-couplings are then computed for each conformational state, and these are used directly to decompose the experimental J-value into contributions from each RIS. Accuracy is enhanced by calculating average J-values for the RIS states. Thus, the MD simulations are used to locate the significant states, but their populations are determined from the experimental J-values.

---

9. "Discrimination between two binding modes of diacylglycerol (DAG) and DAG-lactones to protein kinase C"

Megan Peach
Laboratory of Medicinal Chemistry, National Cancer Institute, NIH

Protein kinase C (PKC) isozymes play important roles in many cell-signaling processes, and are involved in both cell differentiation and cell proliferation. Previous work in this lab has focused on the development of new drug-like ligands for PKC by improving on its natural regulatory agonist, diacylglycerol (DAG). Computational docking studies with these new DAG-like ligands have given conflicting results depending on the program used for docking, and have shown two possible binding modes. Although these two modes appear very similar, experimental binding affinity data suggest that PKC is capable of discriminating between them. The goal of this modeling project was to examine these two binding modes more closely, to determine which orientation is more favorable. We found that the two binding modes are not energetically equivalent, and that the shape of the binding site controls the mode of binding, which varies depending on the structure of the ligand. This work illustrates the need for caution when interpreting the results from docking programs, and shows how a relatively simple analysis can allow deduction of the correct binding mode.

---

10. "Investigating the Origin of Regio- and Stereoselectivity in the Cyclooxygenase-Mediated Oxygenation of Arachidonic Acid"

Derek Pratt
Department of Chemistry, Vanderbilt University

Abstract coming soon...

---

11. "Quantifying the role water plays in protein-ligand binding."

Sarah Wittkopp
Complex Carbohydrate Research Center, University of Georgia

Abstract coming soon...

---

"MDDisplay: An Open Source, Multi-platform, Open GL based Molecular Dynamics Trajectory Viewer"

Chris Moth
Department of Chemistry, Vanderbilt University

Abstract coming soon...

---

---

Sponsored by: