Unfortunately, computing accurate free energy profiles along physical association pathways, let alone the binding kinetics is extremely complex. Long sampling times, significant conformational changes of the target protein and shortcomings with current ligand force-fields concur in frustrating the long ongoing efforts.
Here I report on our efforts in combining approaches based on metadynamics [1,2] together with multiple-replicas [3] and path-sampling [4] can be used to converge the free energy profile along a physical association pathway, to quantify the effect of large-scale conformational changes [5] and to compute binding kinetics with (force-field permitting) reasonable accuracy.
[2] Sutto, L.; Marsili, S.; Gervasio, F. L. WIREs Comput Mol Sci doi:
10.1002/wcms.1103 2012.
[3] Bussi, G; Gervasio, F.L.; Laio, A.; Parrinello, M. J Am Chem Soc
2006, 128, 13435-13441.
[4] Saladino, G; Juraszek, J.; van Erp, T.; Gervasio, F.L. submitted to PRL
[5] Lovera, S; Sutto, L; Boubeva, R; Scapozza,L; Dolker,N and
Gervasio, F.L. J Am Chem Soc 2012, 134, 2496
[6] D’Abramo, Rabal, Oyarzabal, and Gervasio Angew. Chem. Intnl. Ed.
2012, 51, 642-646