DOMAIN MOTIONS IN DIHYDROFOLATE-REDUCTASE - A MOLECULAR-DYNAMICS STUDY

Molecular dynamics simulations have been carried out on the enzyme dih ydrofolate reductase from Lactobacillus casei complexed with methotrex ate, NADPH and 264 crystallographic water molecules. Analysis of corre lations in atomic fluctuations reveal the presence of highly correlate d motion (correlation coefficient > 0.6) in the region between residue s 30 to 35 and 85 to 90 leading to the identification of two domains, an ''adenosine-binding domain'' and a ''large domain'', which rotate b y 3 to 4 degrees with respect to each other. The strongest correlation (>0.6) within the large domain involves a coupling between the motion s of the ''teen-loop'', and the spatially contiguous loops linking bet a 6-beta 7 and beta 7-beta 8. Moreover, there is a significant correla tion (similar to 0.5) between the adenosine fragment of NADPH and the pteridine and p-aminobenzoyl fragments of methotrexate, which are sepa rated by similar to 17 Angstrom, and is lost on removal of ''rigid-bod y'' 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 coenzy me can affect methotrexate binding and vice versa. Quasiharmonic vibra tional analysis of the trajectory reveals that the overall dynamics of the system are governed by domain motions whose contributions are dom inant at low frequencies. In addition, different low-frequency modes a re responsible for separately coupling the adenosine-binding site and parts of methotrexate. (C) 1997 Academic Press Limited.