Gutiérrez de Terán lab
Our research activity is driven by a deep interest in understanding how molecules modulate biochemical processes, and use this knowledge to optimize molecular design. To achieve this goal, we develop our own computational methods for modeling and simulation of membrane receptors, the main target of our studies, as well as computational protocols to quantify and optimize the energetics of biochemical processes, including protein-ligand binding, protein-protein interactions or protein stability. Application of these computational approaches are conducted in collaborative projects, in the framework of pharmacology or biotechnological applications.
Popular science presentation
Computational simulations of biological molecules, such as proteins or nucleic acids, have become a key technique within the fields of bioengineering and pharmaceutical drug design. Based the same principles of statistical mechanics that we teach to our students of technical and natural sciences, we can accurately model the molecular interactions governing the association between i.e. a drug bound to its pharmaceutical target, guiding the development safer pharmaceuticals.
The research activity of our lab includes the development of computationally efficient methods to accurately describe molecular interactions, in combination with advanced statistical and machine-learning models. We interconnect these methods with our deep interest in G protein–coupled receptors (GPCRs), the major family of pharmaceutical targets accounting for more than 30% of the current drugs on the market, by developing predictive models for precision modulation of GPCRs, which ultimately enable more selective therapeutic profiles. With this perspective we are contributing to the development of novel cancer immunotherapy strategies with small molecules, or assist on the design of novel neuroprotective agents, in close collaboration with medicinal chemists and pharmacologists. We have also adapted our computational pipeline to help elucidating the molecular effects of protein mutations, focusing on pathogenic variants responsible of diseases and expanding to applications on drug resistance or protein engineering.
Research projects
The research of the Gutiérrez-de-Terán lab is conducted between Uppsala University and CSIC (Spanish National Research Council), where the PI is lab head of Computational Biochemistry at the Health Research Institute in Asturias. Our research projects include
- Computational models to predict the Effect of mutations on the structure or function of proteins. Point mutations can affect the folding, structure, or function of a protein in a variety of ways. The effects can also be varied: from pathogenic mutations to causing drug resistance in various chemotherapy treatments in oncology or infectious diseases. Over the years, our lab has developed and optimized the open-source, physics-based protocol for in silico mutagenesis, QresFEP. In the last years, we have complemented this effort with a new approach based on machine learning (ML) including graph neural networks (GNN) and protein language models. This research is conducted in close collaboration with the Åqvist lab.
- Modeling and simulation of membrane proteins. Our lab is responsible of the Uppsala-based web server GPCR-ModSim, a service that allows the structural modeling and MD simulation of membrane proteins. The server generates the associated AlphaFold model from any membrane-protein sequence, including (hetero)multimers, and can send this or any experimental structure to its exclusive molecular dynamics (MD) protocol that produces a membrane-embedded, solvated, and equilibrated system, ready to be used as a starting point for further MD simulations, including ligand-binding free energy calculations.
- Free Energy methods for ligand screening and optimization. Over the past years, our team has been working on a major upgrade to QligFEP, our open-source framework for relative binding free energy (RBFE) calculations. The code of QligFEP is also open-source and this development is a result of a collaborative effort with the Åqvist lab and the Jespers lab at Groningen.
- New strategies in cancer immunotherapy based on polypharmacology. This project addresses the characterization and therapeutic intervention of the A2B adenosine receptor, a G protein-coupled receptor (GPCR), within a multi-target strategy that includes other members of the purinergic signaling pathway commonly altered in various tumors. This is a collaborative project coordinated at the ComBio lab at ISPA.