Efficient calculation of enzyme reaction free energy profiles using a Hybrid Differential Relaxation Algorithm. Application to Mycobacterial Zinc hydrolases.

MARTÍN MARIANO; ROMERO JUAN MANUEL; RAMIREZ LILIAN CLAUDIA ; DUMAS MARÍA VICTORIA; MARTÍ MARCELO ADRIÁN

Advances in Protein Chemistry and Structural Biology

Elsevier

Año: 2015

1876-1623

etermination of the Free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme´s catalytic power at the molecular level. Although hybrid, mostly DFT based, QM/MM methods have been extensively applied to this type of studies, achieving accurate and statistically converged results at a moderate computational cost is still an open challenge. Recently, we have shown that accurate results can be achieved in less computational time, combining Jarsynzki´s relationship with a hybrid differential relaxation algorithm (HyDRA), which allows partial relaxation of the solvent during the non-equilibrium steering of the reaction. In the present work, we have applied this strategy to study two Mycobacterial Zinc hydrolases. Mycobacterium tuberculosis infections are still a worldwide problem and thus characterization and validation of new drug targets is an intense field of research. Among possible drug targets, recently two es