Lecture on metadynamics

Predicting the thermodynamic and kinetic properties of the binding process of a drug to its target is of primary relevance to shed light on its mechanism of action and develop new medications [1,2,3]. Here, I illustrate how this information can be obtained from advanced calculations. In particular, we studied the binding of benzamidine to trypsin using a new approach, called Funnel-Metadynamics (FM) [4]. This method enhances the exploration of the ligand bound poses and its solvated states leading to an accurate estimation of the protein-ligand binding free energy. Furthermore, we could recover from metadynamics the kinetic rates of the ligand binding process (koff) using a recently developed protocol [5]. In our simulations, the x-ray conformation was found as the lowest energy pose and the computed ligand binding free energy in good agreement with experiments. Our approach allows also to unveil precious details of the docking process, such as the presence of alternative binding modes and the solvent role. Albeit very recent, FM has proven to be successful in studying complex ligand/protein, ligand/DNA and peptide/membrane interactions [6,7,8]. Finally, I present a very recent protocol that combines multiscale and enhanced sampling methods (coarse-grained/metadynamics) to simulate long time-scale events in very large systems [9]. Using such approach the dimerization mechanism in membrane of the transmembrane helices of the epidermal growth factor receptor has been energetically and structurally characterised, shedding light on possible activation pathways of the receptor. Our protocol allows reaching the second time scale, opening new opportunities to study protein clusters in membrane (e.g. GPCRs, ion channels) and protein/protein interactions (e.g. antigen/antibody) in more physiological environment.

References
1. Limongelli V et al. Proc. Natl. Acad. Sci. USA 107, 5411-5416 (2010)
2. Limongelli V et al. Proc. Natl. Acad. Sci. USA 109, 1467-1472 (2012)
3. Di Leva F, Novellino E, Cavalli A, Parrinello M, Limongelli V. Nucleic Acids Research (2014)
4. Limongelli V, Bonomi M, Parrinello M. Proc. Natl. Acad. Sci. USA 110, 6358-6363 (2013)
5. Tiwary P, Limongelli V, Salvalaglio M, Parrinello M. Proc. Natl. Acad. Sci. USA 112, 386-91 (2015)

6. Troussicot L, Guilliere F, Limongelli V et al. J. Am. Chem. Soc. 137, 1273-1281 (2015)
7. Bruno A,..., Limongelli V. Sci. Rep. 5, 9200 (2015)
8. Comitani F, Limongelli V, Moleni C. J. Chem. Theory Comput. 12:3398-3406 (2016)
9. Lelimousin M, Limongelli V, Sansom MSP. J. Am. Chem. Soc. 138, 10611-10622 (2016)