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 corrins 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 novel structures and subsequently verifying the predictions by X-ray structure determination. The force field has been useful in relating details of the structures of alkylcobalamins to the lability of the Co-C bond towards bond homolysis, probing the conformational flexibility of the 5'-deoxyadenosyl ligand in adenosylcobalamin (AdoCbl, coenzyme B-12), and studying the conformation 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 simulated annealing (SA) procedures. This methodology permits for the first time a detailed description of the motions of cobalt corrins in solution. The consensus structures of SA calculations agree well with the known solid state structures of two complete cobalamins (CH(3)Cbl and CNCbl), including, importantly, the corrin fold angle. The base-off analogs have significantly smaller corrin fold angles, implying that base-on Cbls are under steric strain. These observations lend credence to proposals for the enzymatic labilization of the Co-C bond involving upward flexing of the corrin ring. Preliminary results on the modeling of coenzyme B-12 (AdoCbl) in solution are reported. (C) 1999 Elsevier Science S.A. All rights reserved.