INPhINIT Incoming Fellowship – Development of a FRET-based simulation strategy to unravel binding sites in proteins
GROUP LEADER
Prof. Carles Eduard Curutchet Barat
carles.curutchet@ub.edu
carles.curutchet@ub.edu
RESEARCH PRODUCT / RESEARCH GROUP
Website of Curutchet’s research group. It includes the latests news related to the research of the group (blog), as well as publications, current and previous members, etc.
POSITION DESCRIPTION
Research Project / Research Group Description
The Förster resonance energy transfer (FRET) technique is widely used to measure distances and monitor structural changes in biosystems, due to the strong dependence of FRET efficiency on the mutual arrangement between donor and acceptor fluorophores. FRET involving drugs and Tryptophan has also been extensively used to study ligand-protein binding, for example, to determine binding affinities, but in this case, the constrained orientation of the probes precludes assuming isotropic rotational freedom, thus limiting its ability to inform on the location of the binding site. If experiments are complemented with molecular simulations, however, the lack of orientational freedom can turn into an advantage, as it can allow resolving binding modes characterized by similar distances but different orientations of the ligand. The present project will focus on the application of FRET simulations to study the binding of small ligands to proteins. The computational methods used will be based on the state-of-the-art polarizable quantum/molecular mechanical (QM/MM) method for energy transfer developed in the lab of Prof. Curutchet (Curutchet et al. J. Am. Chem. Soc. 2011, 133, 3078; Curutchet & Mennucci, Chem. Rev. 2017, 117, 294). Curutchet’s lab is part of the Computational Biology and Drug Design (CBDD) group of the University of Barcelona, which enjoys a highly interdisciplinary environment, where the research of Prof. Curutchet on photoinduced processes in biosystems is complemented with the labs of Prof. F. J. Luque and Prof. X. Barril, which combine both experimental techniques and biosimulation to relevant problems of biomedicine and drug design. The CBDD group enjoys funding both from National and European agencies (FRAGments training NETwork, H2020-MSCA-ITN-2015, Project 675899) and a variety of collaborations with private companies like Gaussian Inc., Pharmacelera S.A., Repsol YPF S.A., Avizorex Pharma SL and Minoryx Therapeutics.
Job position description
The position will involve extensive training in classical Molecular Dynamics (MD) techniques as well as in polarizable QM/MM calculations of excited states in biosystems. Prof. Curutchet is an official collaborator of the Gaussian Inc. company, developer of the Gaussian code, probably the leading software in Quantum Chemistry. Thus, the candidate will have access to the expertise of Gaussian developers as well as to the internal development version of the code, in which the QM/MM models of Curutchet lab are implemented (see for example a recent collaboration with Gaussian scientists: Curutchet et al. J. Chem. Theory Comput. 2018, 14, 1671). The project will also be supported by current funding from Curutchet’s lab on this topic (Spanish Ministerio de Economía y Competitividad – Project CTQ2017-89924-P, 2018-2020). On the other hand, the candidate will be offered the possibility to perform secondments and temporary stays in other collaborating institutions, like the previously mentioned Gaussian Inc. company (Wallingford, CT, USA) or the lab of our collaborator Prof. Benedetta Mennucci (University of Pisa, Italy), who has received important European funding on related topics (EnLight ERC-2011 Starting Grant, LIFETimes ERC-2017 Advanced Grant). Moreover, the candidate will have access to the expertise of the other research groups of the CBDD, most notably to the lab of Prof. Xavier Barril, an expert in the discovery of druggable sites in proteins and in structure-based drug design, whose students share the same office space with the students of Prof. Curutchet group. The project will start from previous results of the group on FRET in protein-ligand complexes (Pinheiro & Curutchet, J. Phys. Chem. B 2017, 121, 2265), and is expected to provide a novel promising route to the determination of binding sites and binding modes beyond more costly techniques like X-ray crystallography, which sometimes fail to solve the structure of a given complex.
OTHER RELEVANT WEBSITES
Web site of the Computational Biology and Drug Design group of the University of Barcelona, which is jointly formed by the independent labs of Prof. Curutchet, Prof. F. Javier Luque and Prof. Xavier Barril.
http://www.ub.edu/cbdd
http://www.ub.edu/cbdd