Comparing and combining implicit ligand sampling with multiple steered molecular dynamics to study ligand migration processes in heme proteins.

FLAVIO FORTI; LEONARDO BOECHI; DARIO A. ESTRIN; MARCELO A. MARTI

JOURNAL OF COMPUTATIONAL CHEMISTRY

JOHN WILEY & SONS INC

Año: 2011 p. 2219 - 2231

0192-8651

Abstract: The ubiquitous heme proteins perform a wide variety of tasks that rely on the subtle regulation of theiraffinity for small ligands like O2, CO, and NO. Ligand affinity is characterized by kinetic association and dissocia-tion rate constants, that partially depend on ligand migration between the solvent and active site, mediated by thepresence of internal cavities or tunnels. Different computational methods have been developed to study these proc-esses which can be roughly divided in two strategies: those costly methods in which the ligand is treated explicitlyduring the simulations, and the free energy landscape of the process is computed; and those faster methods that useprior computed Molecular Dynamics simulation without the ligand, and incorporate it afterwards, called implicitligand sampling (ILS) methods. To compare both approaches performance and to provide a combined protocol tostudy ligand migration in heme proteins, we performed ILS and multiple steered molecular dynamics (MSMD) freeenergy calculations of the ligand migration process in three representative and well theoretically and experimentallystudied cases that cover a wide range of complex situations presenting a challenging benchmark for the aim of thepresent work. Our results show that ILS provides a good description of the tunnel topology and a reasonable approx-imation to the free energy landscape, while MSMD provides more accurate and detailed free energy profile descrip-tion of each tunnel. Based on these results, a combined strategy is presented for the study of internal ligand migra-tion in heme proteins.