Conformational stability of Met20 loop of DHFR: A molecular dynamics study

Abstract

In the catalytic cycle of dihydrofolate reductase (DHFR), the conformational change of the Met20 loop plays an important role. There are known to be two stable conformations (closed and open states) in the conformational change of the Met20 loop before binding the substrate. However, the conformational stability of these states is still not clear. In this study, we carried out two molecular dynamics simulations corresponding to the closed and open states of DHFR and estimated the free energy of each state of DHFR by using the molecular mechanics-Poisson Bolzmann surface area (MM-PBSA) method. Although the free energy calculations showed the closed state of DHFR was more stable in the solution condition, the difference of free energies between the closed and open state showed the large deviation. This finding shows that the conformational transition between the closed and open state of the Met20 loop could occur frequently under the solution condition. The frequency distributions along the reaction coordinate was calculated to find the possible metastable conformations, indicating that six metastable conformations exist between the closed and open states.