Jiali Gao, Fellow

Computer Simulations of Chemical and Biochemical Systems in Solution

In this group, a multi-faceted computational project is directed to the study of:

• The dynamics and mechanism of enzymecatalyzed reactions
• The structure and interactions of membrane proteins
• Solvent effects on chemical reactions and interactions in condensed phases

The approach adopted by the group was based on statistical mechanical Monte Carlo and molecular dynamics simulations, making use of a combined quantum mechanical and molecular mechanical (QM/MM) potential.

The first project area involves research into a variety of enzymatic reactions, making use of combined QM/MM methods in molecular dynamics simulations. The group has completed the hydride transfer reaction catalyzed by alcohol dehydrogenase, zylose, and methylamine dehydrogenase, as well as the dihydrofolate reductase reaction path. On-going research involves the human protein tyrosine phosphatase B (PTP1B), squalene cyclases (involved in cholesterol biosynthesis), decarboxylation reactions catalyzed by orotidine phosphate decarboxylase and pyruvate decarboxylase, and hydride transfer reactions catalyzed by dihydrofolate reductase and acyl-CoA dehydrogenase. These studies provide a deeper understanding of enzyme-substrate interactions and can help to better design cholesterol-lowering drugs and therapeutic agents for treatment of cancer, diabetes, and obesity.

The second project area is aimed at the prediction of three-dimensional structures of membrane proteins by making use of nuclear magnetic resonance results, and at the understanding of protein-lipid membrane interactions. This project’s computational details are similar to those of a previous study done by this group involving the protein bacteriorhodopsin. The group is also interested in the theoretical study of processes involving electronically excited states in proteins. These include the effects of mutation on spectral tuning of rhodopsin and the sensory protein, photoactive yellow protein.

The third project area focuses on the development of novel computational techniques in combined QM/MM calculations and applications to modeling the hydrolysis of model compounds for glycosyl derivatives and solvent effects on hydride transfer reactions as models for enzymatic processes. The study of solvents is important in the understanding of the reaction mechanism of organic reactions. The group modeled organic reactions having large solvent effects. The reactions also served as model systems for enzymatic processes. The two reactions the group studied were the hydrolysis of α-methoxy tetrahydropyranoside and the hydrolysis of methyl phosphate. The first reaction is a model compound for the reaction of glycosyl derivatives; the second is a model for kinase and phosphatase catalysis. These simulations used QM/MM Monte Carlo simulations, typically involving 5–10 x 107 configurations.

Research Group and Collaborators

Cristobal Alhambra, Research Associate
Kyoungrim Kate Byun, Research Associate
Elena Cubero, University of Barcelona, Spain
Yao Fan, Graduate Student Researcher
Mireia Garcia-Viloca, Research Associate (Fulbright Fellow)
Maegan Harris, Graduate Student Researcher
Gary S. Kedziora, Research Associate
Lakshmi Kesavan, Graduate Student Researcher
Shuhua Ma, Research Associate
Heather Meads, Undergraduate Student Researcher
Yirong Mo, Research Associate
Kevin Naidoo, Visiting Researcher
Kwamgho Nam, Graduate Student Researcher
Tina Poulson, Research Associate
Ramakumar Rajamani, Graduate Student Researcher
Setu Roday, Albert Einstein College of Medicine, New York, New York