Our research program focuses upon the application and development of new computational tools that target organic and enzymatic catalyst design, alternative environmentally friendly solvent design, and drug discovery. Fundamental problems in organic and medicinal chemistry are probed, such as elucidation of enzymatic reactions, controlling enantioselectivity for chiral compounds, transition structure prediction, de novo design of high-affinity inhibitors, and origins of drug resistance. Obtaining quantitative success with large-scale quantum and molecular mechanical calculations involves the development of improved force fields, software, and methodology.
Background: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS),
a disease of pandemic proportions that has killed an estimated 25 million people and remains one of the leading world-wide
causes of infectious disease related deaths. HIV-1 can be effectively suppressed with current antiretroviral therapy, but
tragically most individuals unable to continue treatment have a rapid rebound in plasma viremia. One explanation for this
observation is the persistence of the virus in long-lived reservoirs, which may include macrophages.
Macrophages are antigen-presenting cells that are critical to the innate immune response against pathogens. However, the infection of these cells by intracellular microorganisms, such as HIV-1, may result in significant pathogenesis to the host. It is known that the interaction between cyclophilin A (CypA) and HIV-1 capsid (CA) in human target cells has been shown to be important for infectivity of the virus. What is not clear is the role of CA-CypA in HIV-1 infection of and replication in macrophages, which appears quite different than in T cells. In addition, binding by cyclophilin B (CypB) to HIV-1 Gag/CA is also unique contrasted to CypA and may have a synergistic effect. A lack of such knowledge is detrimental in the creation of effective anti-HIV compounds.
Objective: The long-term goal is to produce a cyclophilin-based therapeutic treatment effective at impeding the transmission of HIV. Our objective is to construct small molecule leads, based on mimics of cis proline, that display activity against CypA/CypB and to study their efficacy in preventing HIV-1 infection and replication in various cell types. The rationale for our research is that, the creation of compounds specific to Cyp should aid in elucidating the differences in cyclophilin-dependent HIV-1 infection in macrophages as compared to CD4+ T cells. We hope to eventually exploit these pathways with novel antiretroviral strategies.
Solvent Effects and Catalysis
Background: The effect of solvent on chemical transformations is highly sensitive,
typically giving noticeable improvement in rate acceleration and stereoselectivity when
transferring from water to dipolar aprotic solvents. Many substitution and elimination
reactions owe this acceleration to a greater charge differential stabilization of
charged substrates and more charge delocalized transition structures via hydrogen bonding
in protic solvents which is not possible in aprotic ones. The high catalytic efficiency
of enzymes is due to in part to a similar destabilization by extraction of the reactants
from water into the low-dielectric pocket of the binding site. To gain a deeper appreciation
of enzymatic catalysis, it is essential to understand the properties and structure of the
transition structure. The focus of our work is to shed light on the role of transition
states in enzymatic catalysis, by formulating a better understanding on how the immediate
molecular environment surrounding the transition structure affects the rate and selectivity
of fundamentally important reactions.
Objective: The aim is to develop and use computational methods to gain physical insight into how external factors (enzymes or solvent) enhance the rate or stereoselectivity of chemical reactions. For many reactions the role of solvent has been assumed to be static, hence its effect is basically thought to be a contribution of solvation energy to the total free energy of the system. However, direct participation of solvent molecules may occur in which a few critical solvent molecules bind to the transition structure and lower the activation energy or an electric field created by the solvent changes the shape of the potential energy surface. In extreme cases the reaction path itself can be perturbed, especially when Lewis acids are involved. This reinforces the need for thorough studies on the intermolecular interactions occurring between solvents, catalysts, and reactions.
Background: The U.S. chemical industry is the world’s largest producer of chemicals products
(value shipped, $438.8 billion in 2000), contributing the third largest trade surplus
of any non-defense-related sector to the U.S. economy, and representing 10 percent of
all U.S. manufacturing. Chemical companies depend upon volatile organic solvents that
are damaging to the environment, expensive to use and manage, and create safety issues
in production. It has been estimated that over 100 million pounds of chemical waste is
treated yearly, costing industry billions of dollars. As the need for more efficient and
cleaner technologies becomes increasingly important, the search for alternatives to the
most costly and environmentally damaging solvents is becoming an immediate priority. One
promising possibility is the use of room temperature ionic liquids.
Ionic liquids are a novel class of solvents, defined as a material containing only ionic species, with a melting point at or below room temperature. In sharp contrast to molten salts or melts, ionic liquids can be fluid at temperatures as low as 204 K, are colorless, have low viscosities, high conductivity, negligible vapor pressure, excellent thermal and chemical stabilities, are recyclable, non-explosive, easy to prepare, active at room temperature, and tolerate impurities such as water. An exciting aspect of ionic liquids resides in their ability to provide increased rates and selectivity for a series of industrially and academically important reactions such as the Heck, Friedel-Crafts, isomerizations, hydrogenation, organometallic, Michael, Mannich, Wittig, 1,3-Dipolar additions, aldol and benzoin condensations. The observed effects of ionic liquids range from weak to powerful, but an understanding of the molecular factors are largely unknown.
Objective: The objective is to understand the microscopic details on how ionic liquids operate and to exploit this understanding to predict new ionic liquids that give optimal rate and stereoselectivity enhancements. A comprehensive understanding on how ionic liquids impact chemical reactivity will be used to influence a wide range of (1) difficult organic reactions, which benefit from toxic solvents coupled with high pressures and temperatures, and (2) enzymatic reactions, which require complex physiological conditions. The long-term intent of our research program is to create controllable, efficient, safe, and environmentally clean technologies that impact society and chemistry from the laboratory bench top to large-scale industrial manufacturing.
Background: A GPU (graphics processing unit) is a graphic chip that processes the visual
display in a computer. Over the years, these graphic chips have dramatically increased in computing
power due to high demand from the consumer videogame market. As a result, GPUs have become very
attractive for general purpose scientific and engineering computing. GPUs cost a fraction of a
regular computer processing unit (CPU) and can provide dramatic enhancements, e.g., 100x the
processing power per dollar spent. Consequently, 3 of the top 5 supercomputers in the world
are NVIDIA GPU-based computers. The major disadvantage is that software must be rewritten to
utilize GPUs. NVIDIA has introduced a massively parallel architecture called "CUDA" which is
fully programmable for scientific applications, but requires expertise.
Objective: The objective is to routinely simulate large systems containing millions of atoms and thousands of residues. We propose the creation of a new program, MCGPU (Monte Carlo on Graphics Processing Units), to take advantage of the dramatic power of the GPU. Development of MCGPU has begun and individual subroutines have been completed. For example, functions to run a Monte Carlo simulation on a box of solvent molecules using NVT and NPT ensembles and periodic boundary conditions have been coded. The CUDA enabled code can perform a speed up of easily an order of magnitude relative to the single-processor CPU code. When a stable version of MCGPU is completed, is will be distributed as a freely-available, open source program for academic groups.
• NSF, National Science Foundation (CHE-1149604)
• Alabama Supercomputer Center
• Auburn University