MOLECULAR DYNAMICS SIMULATION OF POINT MUTATIONS OF ARG 221 IN THE ACTIVE SITE OF PROTEIN TYROSINE PHOSPHATASE 1B

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is one of the important regulators of signal transduction pathways. The present study aims to investigate the effect of Arg 221 on the active site of PTP1B. Six mutants were carried out using Schrödinger Suite 2007 and molecular dynamics simulation was performed by using the Tinker package. Results show that point mutations at position 221 have great influence on shape of active site, backbone movement of active site, and interaction between substrate and PTP1B. R221H and R221K lead to increased total interaction energies. R221G, R221F and R221T cause increase in total interaction energies, but decrease in interaction energies between pTyr 4 and P loop (catalytic residues). R221E results in both decreased total interaction energies and interaction energies between pTyr 4 and P loop. This indicates that Arg 221 mutated to basic residues can lead to enhanced binding affinity between substrate and protein; when mutated to acidic residues it will decrease binding affinity and catalytic activity; other kinds of mutations result in increased binding affinity but decreased catalytic activity.