Summary of past and present activities

• Effector specificity of Ras isoforms: Interesting insights into the structural behavior of the Ras isoforms are emergingi. Collaboration with an experimental group with many years of experience in Ras proteins has been established. The experiments so far performed are in excellent agreement with our predictions, and are opening up exciting opportunities for a continued collaboration.

• Acetyl cholinesterase tetramer domain motion and its role in the rate of binding of acetylcholine: Using all-atom molecular dynamics simulations, a coarse-grained model is being developed to characterize the long-time scale motions of the tetramer (2600 residues long). Subsequently, Brownian dynamics simulations will be used to calculate the rate constant of acetylcholine binding using multiple structures derived form the above procedure.

• Membrane insertion of lipid-modified Ras peptides: This project involved developing a method for facilitating peptide insertion into lipid bilayers and investigating the biologically highly relevant question of how Ras proteins partition between the cell cytosol and the plasma membrane.

• Investigating the dynamics of beta-secretase, an Alzheimer’s-related enzyme: This project explored, using computational tools, the substrate binding site plasticity of the enzyme. The results published led to collaboration with researchers at in the pharmaceutical industry.

• Investigating the source of (de)stabilization of a critical loop in prion proteins. Using an in-silico analysis of chimeric mutations, the source of stability in one of two structural signatures of prion proteins and its possible link to species barrier has been investigated.

• Improving the predictive power of continuum electrostatic models in the calculation of ionization equilibria of protein charged groups:- The work showed the significant role of structural variability in the native and the denatured state ensembles for a reliable calculation of thermodynamic properties from structure.

• A related approach was subsequently used in the study of conformational dynamics and calculation of association free energies of protein-DNA systems. These studies were benchmarked with experimental biophysical measurements. Some of the major experiments I have been involved in are protein purification, Circular Dichroism, Fluorescence Spectroscopy and Calorimetry.

• Important differences in the electrostatic potentials at the active site of cold-adapted and mesophilic trypsin isoenzymes have been identified using continuum electrostatic calculations.