Molecular modeling of formate dehydrogenase: the formation of the Michaelis complex.
The formation of the reactive enzyme-substrate complex of formate dehydrogenase has been investigated by molecular dynamics techniques accounting for different conformational states of the enzyme. Simulations revealed that the transport of substrate to the active site through the substrate channel proceeds in the open conformation of enzyme due to the crucial role of the Arg284 residue acting as a vehicle. However, formate binding in the active site of the open conformation leads to the formation of a nonproductive enzyme-substrate complex. The productive Michaelis complex is formed only in the closed enzyme conformation after the substrate and coenzyme have bound, when required rigidity of the binding site and reactive formate orientation due to interactions with Arg284, Asn146, Ile122, and His332 residues is attained. Then, the high occupancy (up to 75%) of the reactive substrate-coenzyme conformation is reached, which was demonstrated by hybrid quantum mechanics/molecular mechanics simulations using various semiempirical Hamiltonians.
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University , Leninskie Gory 1, Bld. 73, Moscow, 119991, Russia.
Dmitry K
DK
Nilov
Ivan G
IG
Shabalin
Vladimir O
VO
Popov
Vytas K
VK
Svedas
D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D005560:Formate Dehydrogenases / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
D005560:Formate Dehydrogenases