Computational Molecular Design for Applications in Disease Treatment, Renewable Energy, and Countering Bioterrorism

This research focuses on the application of molecular modeling to meet three pressing current needs: disease treatment, renewable energy, and countering bioterrorism. First, we seek to design therapeutic compounds to treat neglected tropical diseases, including tuberculosis and malaria, using computational screening of large compound libraries. Second, we are designing novel enzymes to catalyze the degradation of lignocellulose, an abundant plant material that is a precursor to biofuels. Third, we are discovering small molecules to inhibit high-priority pathogens that represent a significant bioterrorism threat, for instance, smallpox viruses. We are also designing protein receptors that detect and scavenge lethal nerve agents.

Project Goals

Project goals vary according to the subprojects outlined in the Project Description.

Disease Treatment: The research assistant will computationally discover a set of small, druglike lead compounds that have high-affinity binding to the active sites of key enzymes in Trypanosoma brucei (causative agent of sleeping sickness), in drug-resistant strains of Mycobacterium tuberculosis (causative agent of tuberculosis), or other pathogens of interest. Time permitting, these lead compounds will be optimized for greater potency.

Renewable Energy: The research assistant will computationally redesign microbial enzymes that catalyze the degradation of lignocellulose to bio-ethanol in order to thermostabilized the enzymes. Through thermostabilization, the enzymes will have longer half-lives and resist unfolding at high, industrially relevant temperatures.

Countering Bioterrorism: The research assistant will computationally design a set of small-molecule inhibitors of enzymes necessary for the reproduction of drug-resistant Yersinia pestis, Variola major, or Arenaviruses, Category A bioterrorism agents that cause plague, smallpox, and hemorrhagic fever, respectively. Alternatively, the research assistant will design a protein receptor that binds with high affinity to analogs of sarin, VX, or soman, which are lethal nerve agents. Designed proteins may be used for the detection and decontamination of nerve agents used as chemical weapons.

Student Outcomes

Students will gain experience in:

1. performing molecular modeling to solve unmet challenges;
2. searching and reading scientific literature;
3. formulating hypotheses and devising research plans to test hypotheses;
4. analyzing large data sets;
5. determining whether obtained data support hypotheses;
6. writing follow-up reports to serve as the basis for peer-reviewed research articles.

Student Qualifications

• Required Coursework: Completion of two semesters of organic chemistry and one semester of physical chemistry (B CHEM 401); priority given to chemistry majors.
• Recommended Coursework: Completion of the first semester of biochemistry.
• Recommended Skills: Experience using the Linux operating system or ability to learn a basic set of Linux skills.
• Recommended Interests (at least one): Interface between computing and biotechnology, pharmaceuticals, and basic chemical research, Application of modern computing power to solve problems in human health and/or energy, Molecular modeling, Biochemistry, Structural biology.

Student Responsibilities

Run molecular design calculations on a local computer cluster, analyze and organize data, generate informative figures, and compile reports that can serve as the basis for peer-reviewed journal articles.