Group Meetings
Discrete Molecular Dynamics
We widely employ in our studies the DMD algorithm, developped by our group. In a nutshell, DMD advances the system in a series of time increments, corresponding to successive collisions between pairs of particles. Collisions can be ellastic or ineslastic, which allows us to model any potential-energy function. For a more complete description of DMD, click here.
Protein Modeling
| Our group employs the discrete molecular dynamics algorithm (DMD) to perform molecular dynamics (MD) simulations of proteins. DMD is computationally more efficient that classical MD, and conserves the energy of the system. We have developed a hierarchy of proteins models with increasing complexity, in order to assess different properties of proteins. | One-bead model Two-bead model Four-bead model Heavy atom model |
Alzheimer's disease
| Recent in vitro studies have suggested that the ten-residue segment of the amyloyd &beta -peptide (A&beta), Ala21--Ala30, forms a turn-like structure that nucleates the folding of the full-length A&beta protein. To gain a mechanistic insight, we simulate A&beta(21--30) folding using the DMD algorithm and a united-atom model incorporating implicit solvent and a variable electrostatic interaction strength (EIS). We find that A&beta(21--30) folds into a loop-like conformation driven by an effective hydrophobic attraction between Val24 and the butyl portion of the Lys28 sidechain. At medium EIS (1.5 kcal/mol), unfolded conformations almost disappear, in agreement with experimental observations. Under optimal conditions for folding, Glu22 and Asp23 form transient electrostatic interactions (EI) with Lys28 that stabilize the loop conformations. Glu22-Lys28 is the most favored interaction. High EIS, as occurs in the interior of proteins and aggregates, destabilizes the packing of Val24 and Lys28. Analysis of the unpacked structures reveals strong EI with predominance of the Asp23-Lys28 interaction, in agreement with studies of molecular modeling of full-length A&beta fibrils. The binary nature of the EI involving Lys28 provides a mechanistic explanation for the linkage of amino acid substitutions at Glu22 with AD and cerebral amyloid angiopathy. Substitutions may alter the frequency of Glu22 or Asp23 involvement in contact formation and affect the stability of the folding nucleus formed in the A&beta(21--30) region. |
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Protein Folding Kinetics
| There is much to learn from the discernment of the folding pathways that lead the protein from the earlier stages when the peptide resembles a random coil to the final folded conformation. In collaboration with Prof. Eugene I. Shakhnovich we have studied the folding kinetics of the SH3 domain of the viral oncogene product Crk. Our investigations propose a nucleation scenario as the dominant folding mechanism for Crk-SH3 domain, as well as the presence of two kinetic intermediates under suitable environment conditions. |
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| Proteins become thermodynamically unstable at low temperatures and high pressures, a phenomenon called cold denaturation. Phenomenological explanations of cold denaturation have been proposed, but a microscopic understanding of the mechanisms leading to cold denaturation has yet to be clarified. We have studied the cold denaturation process of a water-protein model with qualitative agreement between model and experimental protein phase diagrams. |
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