The structure of cobalt corrinoids based on molecular mechanics and NOE-restrained molecular mechanics and dynamics simulations

Approaches the authors have used for modeling the structure of the cobalt c orrins by molecular mechanics methods are reviewed. A parameter set for use with the MM2 force field has been developed. The structure of the corrins is well reproduced, and the force field has been validated by predicting no vel structures and subsequently verifying the predictions by X-ray structur e determination. The force field has been useful in relating details of the structures of alkylcobalamins to the lability of the Co-C bond towards bon d homolysis, probing the conformational flexibility of the 5'-deoxyadenosyl ligand in adenosylcobalamin (AdoCbl, coenzyme B-12), and studying the conf ormation of coenzymatically active AdoCbl analogs, including one that fails to crystallize. The technique has been further extended to include the use of NMR-derived distance restraints in molecular dynamics (MD) and simulate d annealing (SA) procedures. This methodology permits for the first time a detailed description of the motions of cobalt corrins in solution. The cons ensus structures of SA calculations agree well with the known solid state s tructures of two complete cobalamins (CH(3)Cbl and CNCbl), including, impor tantly, the corrin fold angle. The base-off analogs have significantly smal ler corrin fold angles, implying that base-on Cbls are under steric strain. These observations lend credence to proposals for the enzymatic labilizati on of the Co-C bond involving upward flexing of the corrin ring. Preliminar y results on the modeling of coenzyme B-12 (AdoCbl) in solution are reporte d. (C) 1999 Elsevier Science S.A. All rights reserved.