Domain motions in dihydrofolate reductase: A molecular dynamics study

Molecular dynamics simulations have been carried out on the enzyme dihydrofolate reductase from Lactobacillus casei complexed with methotrexate, NADPH and 264 crystallographic water molecules. Analysis of correlations in atomic fluctuations reveal the presence of highly correlated motion (correlation coefficient > 0.6) in the region between residues 30 to 35 and 85 to 90 leading to the identification of two domains, an ''adenosine-binding domain'' and a ''large domain'', which rotate by 3 to 4 degrees with respect to each other. The strongest correlation (>0.6) within the large domain involves a coupling between the motions of the ''teen-loop'', and the spatially contiguous loops linking beta 6-beta 7 and beta 7-beta 8. Moreover, there is a significant correlation (similar to 0.5) between the adenosine fragment of NADPH and the pteridine and p-aminobenzoyl fragments of methotrexate, which are separated by similar to 17 Angstrom, and is lost on removal of ''rigid-body'' motion from the original trajectory. This provides support for the idea that the relative motion of the two domains is a means by which the occupation of the binding site for the adenosine end of the coenzyme can affect methotrexate binding and vice versa. Quasiharmonic vibrational analysis of the trajectory reveals that the overall dynamics of the system are governed by domain motions whose contributions are dominant at low frequencies. In addition, different low-frequency modes are responsible for separately coupling the adenosine-binding site and parts of methotrexate. (C) 1997 Academic Press Limited.