Università degli Studi di Cagliari
Predicting binding kinetics and free energy profiles of drug receptor complexes from all-atom simulations
05 luglio 2012
Scuola di Dottorato in Fisica
Il Prof. Francesco Gervasio (Spanish National Cancer Research Center, Spain) terrà il giorno giovedì 5 luglio 2012 alle ore 11.00 presso l’Aula C del Dipartimento di Fisica il seguente seminario:
Predicting binding kinetics and free energy profiles of drug receptor
complexes from all-atom simulations
The manipulation of binding kinetics is emerging as a critical parameter to optimize the efficacy and minimize the toxicity of lead compounds in vivo. A computational method able to link the structure of the ligand to the observed binding kinetics would be very valuable.
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.
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.
[1] Laio, A.; Gervasio, F. L. Rep. Prog. Phys. 2008, 71, 126601.
[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
[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