Electronic and Atomic Protein Modelling

Overview:

The theoretical study of functional proteomics requires a complete understanding of the different times scales in biochemical processes. The fast motions, often involving a chemical reaction, might require a time-dependent quantum mechanical description of the active site. The slow motions, responsible for conformational changes, require the description of the biological environment (such as protein-protein interaction, solvent, etc.) and various physical properties (such as temperature, pressure). An accurate description of these different time scales bridges the gap between theoretical and experimental studies.

Our group focuses on the theoretical modeling of these different time scales in order to achieve atomic (and electronic) detailed information of protein biochemistry and biophysics.

RESEARCH DIRECTOR

Guallar, Victor (ICREA Research Professor)

Objectives:

Explore the chemical and physical responses to local and global configuration changes, which may be achieved by coupling a quantum-mechanical description of the reactive process with advanced sampling techniques. For this purpose, several simulation protocols and algorithms, which combine optimized sampling techniques with hybrid QM/MM methods and semiclassical dynamics corrections, are being studied. The objectives are centered in two main areas.

First, we place particular on the application of such methods, with emphasis on protein-substrate interactions and long time protein conformational dynamics. Current application studies include electron transfer and catalysis mechanism studies on heme proteins, fatty acid migration on fatty acid binding protein, Abr-BCL leukemia inhibitors mechanism, etc.
The second area involves the development of new methodological components, focusing on obtaining long time protein dynamics by means of a kinetic Monte Carlo scheme. This area involves mainly the continuous development of our own code PELE.

These two areas provide different venues for students/researchers to explore, based on their strengths and interests. Inquire Prof. Guallar about lab openings!.

Projects/Areas:

Orbital Picture Electron transfer in heme groups. Using mixed quantum mechanics/molecular mechanics techniques (QM/MM) we are investigating the active role of the propionate groups in tunning the porphyrines electronic states. Preliminary results indicate that the propionates groups directly “host” electron transfer pathways.

NO detoxification by globin proteins. In collaboration with Prof. Dennis Rousseau and Prof. Syun-Ru Yeh (AECOM), we are investigating the NO detoxification mechanism in a variety of globin systems.

Allosteric mechanism in Hemoglobin. In collaboration with Prof. Thomas G. Spiro (Princeton University) we are seeking to obtain an atomic detailed view for the allosteric mechanism in human hemoglobin.

Protein Energy Landscape Exploration (PELE). Our code PELE is currently being developed to include a kinetic Monte carlo formalism and a Gaussian Network Modeling (GNM) method. More about PELE: http://spin.wustl.edu/pele/.

Induced Fit Docking. Using PELE, and in collaboration with Schrodinger Inc.(http://www.schrodinger.com/), we are developing induced fit docking algorithms. Application to Leukemia inhibitors is curretly being implemented.