A NEW PROTOCOL FOR DRUG DISCOVERY BASED ON FULLY ATOMISTIC PROTEIN FOLDING SIMULATIONS

by Pietro Faccioli (TIFP)

Wednesday 12 Feb 2020, 14:00 → 15:00 Europe/Rome

Paoluzi (SOGENE)

Enhanced path sampling schemes developed in the last several years have made it possible for the first time to simulate the entire folding transition of proteins consisting of several hundreds amino-acids, using realistic all-atom force fields [1-4]. In the first part of this talk, I will briefly review these computational techniques and discuss their validation against plain MD simulations [3] and optical experiment [4,5].  For illustration purposes I will then show its application to the mis-folding process for two different types of prion proteins [6, 7]. 

The possibility of simulating the entire protein folding and misfolding processes unveils a wealth of new biophysical information. In particular, it enabled us to note some striking conserved regularities which characterize the protein folding transitions of biologically relevant proteins. This discovery paved the door to conceiving an entirely new protocol for in silico drug discovery. This method, denominated Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT) is based on identifying small molecules which can stop the protein folding process, thus triggering its degradation via the cell's quality control. Depending on time availability, I will show how PPI-FIT has been validated by designing different drugs which have been shown to suppress in a dose-dependent way the expression in cell of the human prion protein.  

 

REFERENCES

 

[1] S.  a Beccara, T. Skrbic, R. Covino and P. Faccioli, Proc. Natl. Acad. Sci. USA 109, 2330 (2012)

[2] S a Beccara, L Fant, P. Faccioli, Phys. Rev. Lett. 114, 098103 (2015)

[3] S. Orioli, S. a. Beccara, and P. Faccioli, J. Chem. Phys. 147, 064108 (2017)

[4] F. Wang, S. Orioli, A. Ianeselli, G. Spagnolli, S. a Beccara, A. Gershenson, P.Faccioli and P. L. Wintrode, Biophys. J. 114, 2083 (2018)

[5] A. Ianeselli, S. Orioli, G. Spagnolli, P. Faccioli, L. Cupellini, S. Jurinovich, and B. Mennucci, J. Am. Chem.  Soc., 140, 3674 (2018)

[6] G. Spagnolli et al. PLoS Pathog 15(7): e1007864 (2019)

[7] L. Terruzzi et al. In preparation.