Molecular dynamics simulations of R67 DHFR: Investigation of the cooperative binding

COMP 166

Chuanyin Shi, cshi@odu.edu and Jennifer L. Radkiewicz, jradkiew@odu.edu. Department of Chemistry and Biochemistry, Old Dominion University, 4541 Hampton Blvd., Norfolk, VA 23529
R67 dihydrofolate reductase (R67 DHFR) is a plasmid–encoded enzyme and can catalyze the conversion of dihydrofolate (DHF) to tetrahydrofolate (THF). This is very important for DNA synthesis in the cell. This enzyme has the same function as chromosomal DHFR but has a totally different structure which consists of four identical 78 amino acid strands. Therefore, it relies on a different method for binding and catalysis. The four identical subunits will form a D2 symmetric tetramer, the active site can bind two ligands, and the enzyme exhibits positive and negative cooperativity. We performed molecular dynamics simulations on several complexes, and analyzed the results. The stability of the tetramer and the probability of near-attack conformers will be discussed. Most importantly, the differences in binding contacts between various complexes will be presented. This data will provide useful insights into the unique binding properties of this enzyme.