BAP · A dynamical view of binding affinity
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-10-01 → 2017-09-30
- EU contribution
- €165,599
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
A dynamical view of binding affinity
The human body is a complex machine regulated by thousands of proteins that, like pieces of a puzzle, match together to complete the full picture. For this reason, the study of proteins properties, such as their structure and complementarity nature, is at the basis of our understanding for every biological process happening in cells. Similarly of missing or wrong pieces in a puzzle, perturbations in such precise protein matching system is often the principal cause of disease. For all these reasons, the study and understanding of interaction processes between proteins (i.e., protein-protein complexes) is of fundamental importance for progress. Protein-protein complexes (PPC) can be studied under many different aspects, and one of the most important is their binding affinity. The binding affinity of a PPC is the quantity that define whether or not complex formation occurs, thereby determining its biological relevance. It is therefore a key quantity for understanding and predicting association and dysfunction phenomena. In this scenario, modulating the binding affinity offers great opportunities to control interactions and design innovative therapeutics. My Marie Sklodowska-Curie Individual Fellowship has been focused on the study and prediction of binding affinities in biomolecular complexes, which accurate prediction was still a big challenge in the field. With my research, I could developed a binding affinity prediction that currently outperform any methods propose to date and successfully applying it to protein-ligand complexes as well. The outcomes of those results can be of large and important impact. Fields such as drug design, protein engineering, computational mutagenesis and docking can all benefit from a reliable method to predict binding. In particular, over the past years there is an increasing trend of the pharmaceutical companies towards rational drug design instead of random trials, to cut costs and maximize the percentage of successful drugs developed. My new and accurate approach to predict binding affinity in protein-protein and protein-ligand complexes can be of great interest for companies for the development and design of new drugs.
Data: CORDIS, © European Union
Project objective
Almost all critical functions in the cell rely on specific protein-protein interactions (PPIs). Understanding interactions is therefore a crucial step in the investigation of biological systems and in drug design. Despite all the research efforts that have been devoted to unravel principles of PPIs in the past decades, we still lack a thorough understanding of the energetics of proteins association, which is limiting our ability to consistently predict protein complexes, engineer high-affinity interactions and design new drugs. An improved understanding of protein binding affinity holds the key for resolving some of the most important problems in molecular biology, with wide implications in related fields. In this project I propose a novel approach to reliably predict the binding affinity by adding the so-far neglected dynamical dimension to the problem. Unlike traditional methods like empirical energy-based scoring, I will assess the conservation of interface contacts in protein complexes during dynamics trajectories. By correlating such properties to experimental binding affinities, a new predictor will be developed. Preliminary results on limited set of complexes already indicate that this approach has a great potential, outperforming any predictor proposed to date. Moreover, I will expand this novel approach and assess its applicability to other critical research fields related to biomolecular interactions, such as docking and proteins and interactions engineering. This project will allow me to reinforce and further expand my skills and expertise, create new collaborations and reinforce my position as researcher in Europe, which will enable me to reach full independency in the future.
Original text from CORDIS.
Participants
- UNIVERSITEIT UTRECHT · UtrechtCoordinatorNetherlands
Links
Data: CORDIS, © European Union