Simulations of protein-ligand interactions
Leif BuŸlow and co-workers at the department of applied biochemistry at
Lund university have mutated lactate dehydrogenase in order to change the
coenzyme preferences. We have tried to explain their peculiar results by
molecular dynamics simulations of the native enzyme and an Ile51Lys-Asp52Ser
double mutant [28]. The simulations show that Ser-52 destabilises the binding
of the adenine moiety of coenzyme (a strong hydrogen bond is broken). Yet,
this increases kcat for the mutant, since the dissociation of NAD(P)H is
the rate-determining step in the reaction. KM(NADP+)
is doubled, however, due to that Lys-51 swings out into the solution instead
of interacting with phosphate group as was intended.
Tomas Eklund from the department of organic chemistry has measured the
binding of oligosaccarides to a lectin with microcalorimetry and kinetic
methods. Interestingly, lactose amine binds much stronger than lactose
to the lectin, which is hard to explain with current models. We have performed
molecular dynamics simulations of these systems, and the results indicate
that difference in binding cannot be explained with changes in hydrogen-bond
structure [40]. Probably, global changes in the protein conformation are
involved.