Section: Research Program
Modeling the flexibility of macro-molecules
Keywords: Folding, docking, energy landscapes, induced fit, molecular dynamics, conformers, conformer ensembles, point clouds, reconstruction, shape learning, Morse theory.
Proteins in vivo vibrate at various frequencies: high frequencies correspond to small amplitude deformations of chemical bonds, while low frequencies characterize more global deformations. This flexibility contributes to the entropy thus the free energy of the system protein - solvent. From the experimental standpoint, NMR studies generate ensembles of conformations, called conformers, and so do molecular dynamics (MD) simulations. Of particular interest while investigating flexibility is the notion of correlated motion. Intuitively, when a protein is folded, all atomic movements must be correlated, a constraint which gets alleviated when the protein unfolds since the steric constraints get relaxed (Assuming local forces are prominent, which in turn subsumes electrostatic interactions are not prominent.). Understanding correlations is of special interest to predict the folding pathway that leads a protein towards its native state. A similar discussion holds for the case of partners within a complex, for example in the third step of the diffusion - conformer selection - induced fit complex formation model.
Parameterizing these correlated motions, describing the corresponding energy landscapes, as well as handling collections of conformations pose challenging algorithmic problems.
At the side-chain level, the question of improving rotamer libraries is still of interest . This question is essentially a clustering problem in the parameter space describing the side-chains conformations.
At the atomic level, flexibility is essentially investigated resorting to methods based on a classical potential energy (molecular dynamics), and (inverse) kinematics. A molecular dynamics simulation provides a point cloud sampling the conformational landscape of the molecular system investigated, as each step in the simulation corresponds to one point in the parameter space describing the system (the conformational space) . The standard methodology to analyze such a point cloud consists of resorting to normal modes. Recently, though, more elaborate methods resorting to more local analysis , to Morse theory  and to analysis of meta-stable states of time series  have been proposed.