Research

Research in our laboratory consists of the development and application of computational methods to diverse systems of interest. The research projects are interdisciplinary in nature, including subjects from organic chemistry, physical chemistry, analytical chemistry, inorganic chemistry and biochemistry. The group utilizes various computational tools such as Gaussian 98/03, GAMESS, CHARMM, AMBER, MOE, CAChe, UHBD, NAMD, and DL_POLY. Students in the group interact with faculty members within the Department as well as faculty from Pitt and PSC. Students also work with and visit scientists at IBM Almaden and the Pittsburgh National Energy Technology Laboratory.

CdS Project

Description: This project centers on the structure and electronic properties of encapsulated cadmium sulfide nanoparticles.  Our interest is to understand the fundamental principles that lead to stable, functionalized quantum dots.  The challenge of creating functionalized, robust quantum confined group II-VI semiconductor nanoclusters (NC’s) involves the ability to realize size-controlled and size-stable nanocrystallites. The objective is to provide atomistic-level and fundamental insight into the structure, stability and aqueous assembly of CdS NC’s and of higher-order NC architectures with unique physical properties.

Goals: The goals of this project are to develop and apply computational protocols to study organic and peptide encapsulated CdS nanoparticles.  To achieve these goals we will make use of quantum mechanical methods, molecular mechanical methods as well as Brownian dynamics methods.  Using these computational methods we will explore the structure and electronic properties of these nanoparticles. The broader impacts of the proposed activity efforts focus upon the training and education of future scientists in multidisciplinary sciences, and the impact of providing a novel tool set that will assist scientists in quantum dot research related to information technology.

Publications

• Nunes, S.; Zhou, Z.; Evanseck, J. D.; Madura, J. D. Computational analysis of Cadmium Sulfide (CdS) Nanocrystals” Encyclopedia of Nanoscience and Nanotechnology 2004, MarcelDekker Inc.
• Spreitzer, G. et al. Peptide-encapsulated CdS Nanoclusters from a Combinatorial Ligand Library. Chemical Communications (Cambridge). (3), 209-210.  2000.

Oligosaccharide – Protein Interactions

Description: A multi-disciplinary research project that is exploring sugar – protein interactions and is developing fundamental scientific discoveries and advances leading to a new understanding of biochemistry. This project is a collaborative project between a biochemistry group at the University of South Alabama and here. The computational component being undertaken at Duquesne along with some basic physical characterization experiments.

Goals: The proposed goals of this project are to elucidate the important interactions between oligosaccharides and proteins. This is currently being accomplished using computational methods, such as free energy simulations and docking techniques. Additionally these computations are being supported by isothermal titration calorimetry and fluorescence experiments. This research is trying to understand the role of these proteins has in breast cancer.

Publications

• Aronson, N. N. Jr. et al. Homology Modeling of Glycosyl Hydrolase Family 18 Enzymes and Proteins. Journal of Chemical Information and Computer Sciences. 37(6), 999-1005. 1997.
• Dalal, P et al. Molecular Dynamics Simulations of Oligosaccharide-Protein Interactions. Manuscript in preparation, 2004

CO₂ Sequestration in Brines and Coal

Description: The combustion of fossil fuels releases large amounts of carbon dioxide into the atmosphere, which is known to cause global warming. One idea to get rid of the excess CO2 is to use brine aquifers to sequester the gas by using mineral trapping in brine aquifers, where the CO2 is introduced into solution, converted to carbonate, and associates ionically with metal ions to from insoluble metal carbonates. Our interest is to understand how brines can influence the sequestration of CO2 in brine aquifers. This project is in collaboration with NETL of Pittsburgh and Penn State University.

Goals: The goals of this project are to apply computational techniques to determine the properties under which CO2 may be best sequestered in brine aquifers. FEP/MC simulations are used to determine the solubility of CO2 in various brine solutions and hybrid QM/MM dynamics simulations are performed to look at the conversion of CO2 to carbonate in the presence of high concentrations of ions. Together, these simulations will provide a molecular explanation of the factors that most influence the CO2 sequestration process from a thermodynamic, kinetic, and structural aspect.

Publications

• Dick, T. et al. Molecular basis for carbon dioxide sequestration in coal. Preprints of Symposia - American Chemical Society, Division of Fuel Chemistry, 47(1), 14-16, 2002.
• Dick, Thomas J., et al. Advancements in CO2 Sequestration: Development and Testing of Aqueous Parameters for Carbon Dioxide. Manuscript in preparation.
• Dick, Thomas J., et al. Advancements in CO2 Sequestration: Solubility of CO2 in Brines using FEP/MC Simulations,. Manuscript in preparation.

Metals in Biology

Description: Recent studies have shown that cells use proteins called “metallochaperones” to perform the routing of metal ions to protect the cell and to ensure delivery to nascent enzymes. However, the mechanism of binding and relese of metals by these metallochaperones is not well understood. The largest protein of the copper chaperone family has a common structure known as an “open-faced b-sandwich”, consisting of two a-helices overlaying four b-strands. An exposed –cys-x-x-cys- metal binding motif is positioned in a loop near one end of the protein. A similar motif is seen in the Thioredoxin family of proteins.The cysteinyl thiolates in the Thioredoxin family, with markedly altered pKa’s, serve a catalytic function.

Goals: We are proposing that, as in the Thioredoxin, the thiolates have perturbed pKa’s and these differences are important in the release of the metal ions. A new procedure has been developed to calculate the pKa value of the cysteines in both Thioredoxin and metallochaperones proteins. We use state-of-the art computational chemistry to make such calculations. 

Publications

• Esposito, E. X. et al. Docking Substrates To Metalloenzymes. Molecular Simulation. 24(4-6), 293-306. 2001
• R. R. Radwan et al. Determination of Cysteine pKas in a Copper Chaperone Protein. Manuscript in preparation, 2004.
• R. R. Radwan et al., pKa of metalloproteins ligand, Manuscript in preparation, 2004.

Nitrile Anion Structure and Reactivity

Description: The nitrile functional group is a small, under-utilized unit in organic synthesis. However, it has been demonstrated that this functional group can be used in the synthesis of complex organic compounds. In particular the stereochemistry of cis/trans decalin systems. Fundamental insight on how nitrile anions operate is not fully realized. Computational methods are being applied to study these systems

Goals: The goal is to use ab initio methods to elucidate the role solvent and counter-ions have on the structure and reactivity of nitrile anions and how the solvent and counter-ions can be used to direct the stereochemistry of specific reactions involving nitrile anions.

Publications

• Carlier, P. R. et al. Effective Computational Modeling of Constitutional Isomerism and Aggregation States of Explicit Solvates of Lithiated Phenylacetonitrile. Journal of Organic Chemistry, 67 (11), 3832-3840. 2002

Proteins at Ice/Water Interfaces

Description: Antifreeze Proteins (AFPs) found in fish, plants and insects help the organisms to survive cold temperatures. Various applications of such molecules are in agricultural (grain preservation and transgenic plants), medicine (organ preservation and cryosurgery), aerospace (wing de-icers) and other industries.

Goals: The goal of this project is to apply various computational techniques such as MM, MD and QSAR to elucidate the molecular mechanism of these proteins. As an outcome of this research a more potent antifreeze molecule will be proposed for industrial use.

Publications

• Dalal, P., et al., Hydrogen bond analysis of type 1 antifreeze protein in water and the ice/water interface. PhysChemComm,: Paper No. 7. 2001
• Dalal, P., et al., "Antifreeze" Proteins at the Ice/Water Interface: Three calculated discriminating properties for orientation of Type I proteins. Manuscript in Preparation, 2004.

Proteins and Inorganic Crystals at Lipid/Water Interfaces

Description: This project investigates a) the mechanism of inflammatory diseases such as arthritis and pseudogout and b) the mechanism of protection of lipid membrane by antifreeze proteins. Our interest is to understand the mechanism of interaction of different molecules with lipid membranes.

Goals: The goals of this project are to apply computational techniques to determine the mechanisms of interaction. Specifically, we will use molecular mechanics and molecular dynamics methods to model the interaction between lipid and inorganic crystal such as Calcium Pyrophosphate Dihydrate (CPPD) in order to determine the molecular mechanism of pseudogout. On the other hand similar models involving lipid membranes will be developed to understand the protection offered by such proteins onto the membranes during thermal stress.

Publications

• Wierzbicki, A. et al. Molecular dynamics simulations of crystal induced membranolysis. J. Phys. Chem. B 107, 12346-12351, 2003.
• Dalal, P., et al. Molecular dynamics simulations of inhibition of crystal induced membranolysis. Manuscript in Preparation, 2004.

Melatonin Receptors

Description: This project involves creating structures of G-Protein Coupled Receptors (GPCRs) through a technique called “comparative modeling.” The GPCRs of interest are the melatonin receptors (MT1 and MT2), which belong to the rhodopsin family. Specific, highly conserved motifs of these models that contain key mutations are being analyzed in order to elucidate their function. Currently, there is collaboration between the computational chemistry group and pharmacy group at Duquesne in hopes that this family of receptors can be better understood.

Goals: The goals of this project are to use programs like MOE and Modeller to create structures for the melatonin receptors using rhodopsin as a template model. At the moment rhodopsin is the only GPCR whose structure has been solved through X-Ray Diffraction and NMR methods. Once sufficient models have been created and evaluated through programs such as PROCHECK or 3D-Profiler different motifs will be analyzed using MOE and BioCAChe. Specifically, different ligands will be docked into the models using Grid-based methods.

HIV-RT Inhibitors

Description: HIV-1 reverse transcriptase (RT) is an important target for drugs used in the treatment of AIDS. Drugs known as non-nucleoside RT inhibitors (NNRTI) appear to alter the structural and dynamical properties of RT which in turn inhibit RTs ability to transcribe. Molecular dynamics, principal component analysis and binding free energy simulations are employed to explore the dynamics of RT and its interaction with a bound NNRTI, for both wild type and mutant RT. We show that a bound NNRTI hinders the motion of RT subdomains. Mutations in the non-nucleoside RT inhibitor binding pocket partially restore RT flexibility.

Goals: The goal of this project is to understand the impact of protein dynamics plays in the activity of this enzyme. In addition we are trying to elucidate the mutations play in drug resistance by potentially restoring the required dynamical motion of the enzyme.

Publications

• Zhou, Z. et al. Docking of Non-nucleoside Inhibitors: Neotripterifordin and its Derivatives to HIV-1 Reverse Transcriptase, Proteins: Structure, Function, and Genetics. 49(4), 529-542. 2002
• Zhou, Z. and J.D. Madura Relative Free Energy of Binding and Binding Mode Calculations of HIV-1 RT Inhibitors Based on Dock-MM-PB/GS. In press, Proteins, 2004.
• Zhou, Z., and J.D. Madura, 3D-QSAR CoMFA and Docking Study on HIV-1 RT Non-nuclesodie inhibitors, TIBO derivatives. Submitted JCICS, 2004.
• Zhou, Z., Madrid, M., Evanseck, J., Madura, J. Effect of a bound non-nucleoside RT inhibitor on the dynamics of HIV-1 Reverse Transcriptase, In preparation, Proteins, 2004.

Methane Hydrates

Description: Gas clathrates are viable energy resources. Methane stored in naturally occurring clathrates potentially hold enough methane to ensure supply for many years; methane clathrates are also known to cause blockage in the natural gas pipelines. Clathrates have also been discussed as possible storage sites in CO2 sequestration. Although these have been known about for over a century, there is little known about the clusters on an atomistic scale and what structural properties are critical in the formation and dissipation of gas clathrates.

Goals: The goals of this project are to apply computational techniques to determine the properties under which clathrates may be utilized as effective energy sources. QM calculations are used to determine stable clathrate structures and to calculate the interaction energy between the gas and the clathrate shell. MC simulations map out the phase diagram of the clathrate and provide structural information on the average configurations of the clathrates under their naturally occurring conditions. Together, these simulations will provide an understanding of the formation, dissipation, and gas exchange of clathrates from a thermodynamic and structural viewpoint.

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