Abstract

Membrane receptors are proteins embedded in the cellular membrane. They are the major contributors of the information flow from the outside to the inside of the cell, converting extracellular stimuli in specific cellular processes. Among them, human G-protein coupled receptors (hGPCRs) are arguably the most relevant from a pharmaceutical perspective: they are targets of more than 30% of all approved drugs in the US [1]. However, the usage of computational tools for the rational design of new receptor-targeting drugs with higher affinity and specificity is impaired, in many cases, by the paucity of structural experimental information and by the low sequence identity between members of the receptors' family. As a consequence, only low-resolution models of the protein/ligand complex can be obtained.

In this talk, I will present a multiscale molecular dynamics simulation method, the Open Boundary-Molecular Mechanics/Coarse-Grained approach (OB-MM/CG) [2, 3], which represents a valuable alternative to standard atomistic simulations for the challenging case of such low-resolution models of hGPCRs. Comparisons performed with respect to fully atomistic simulations could assess the reliability of the method and the improvement with respect to previous implementations. Importantly, the OB-MM/CG scheme leads to the simulation of a well-defined statistical ensemble - the grand canonical one - in the high-resolution region allowing, in principle, the calculation of binding free energies. Therefore, the OB-MM/CG scheme paves the way to rigorous drug-design applications even for the challenging case of low-resolution protein models.

References

[1]        A. S. Hauser et al., "Pharmacogenomics of GPCR Drug Targets," Cell, vol. 172, no. 1-2, pp. 41-59, Jan 11 2018.

[2]        T. Tarenzi, V. Calandrini, R. Potestio, A. Giorgetti, and P. Carloni, "Open Boundary Simulations of Proteins and Their Hydration Shells by Hamiltonian Adaptive Resolution Scheme," Journal of Chemical Theory and Computation, vol. 13, no. 11, pp. 5647-5657, Nov 2017.

[3]        T. Tarenzi, V. Calandrini, R. Potestio, and P. Carloni, "Open-Boundary Molecular Mechanics/Coarse-Grained Framework for Simulations of Low-Resolution G-Protein-Coupled Receptor-Ligand Complexes," J Chem Theory Comput, vol. 15, no. 3, pp. 2101-2109, Mar 12 2019.

About The Speaker

Thomas Tarenzi was born in Cremona, Italy, in 1990. He graduated in Chemistry at the University of Parma, with a thesis concerning the synthesis of doubly functionalized peptide nucleic acid monomers. He continued his studies at the University of Florence with a Master in Chemical Sciences; there he developed an outstanding interest in protein function research and in computational biochemistry as a tool to investigate structures, dynamics and interactions of biomolecules.

Thomas is one of the 15 Early Stage Researchers of the European Joint Doctorate Program High Performance Computing in Life Sciences, Engineering and Physics (HPC-LEAP), with joint degree awarding Institutions The Cyprus Institute (CyI) and the Rheinisch-Westfälische Technische Hochschule Aachen (RWTH). The project, entitled "Targeting mosquito GPCRs and malaria transmission", is supervised by Prof. George Christophides and Prof. Paolo Carloni. Thomas successfully defended his PhD in Aachen on 27 March 2019.

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