Dynamics of Large-Scale Protein Conformational Transition and Docking Events using a Hybrid All-Atom Structure Based Model

Abstract

Structure based potentials have achieved a fast description of protein folding by implementing its energy landscape interpretation both at a coarse-grained and all-atom level [Whitford et al. (2009) Proteins: Structure, Function, and Bioinformatics, 75(2), 430-441]. Concerning other kinds of conformational transitions, like allosteric structural modifications, this approach was only applied to coarse-grained representations [Yang S., Roux B. (2008) PLoS Comput Biol 4(3): e1000047; Tripathi, S. and Portman, J. J. (2011) J. Chem. Phys. 135, 075104], thus lacking in accuracy with respect to the local backbone and critical side-chain interactions. The all-atom model we propose for large-scale structural rearrangements in proteins combines a classical forcefield description of the local interactions with a structure-based term for non-bonded interactions. To our knowledge, this is the first application of such a hybrid model [Pogorelov, T. V., and Luthey-Schulten, Z. (2004) Biophysical Journal, 87(1), 207-214; Meinke, J. H. and Hansmann U. H. E. (2007) J. Phys.: Condens. Matter 19 285215] outside the framework of protein folding. A further level of refinement is considered by energetically rewarding, in the structure-based term, functional residues conserved along evolution as yielded by bioinformatics tools. We present the results of this model for: the conformational transition of the so-called activation loop associated with activation for the catalytic domain of human c-Src tyrosine kinase; the assembly of the building modules of c-Src; the docking events of molecular complex partners chosen from the Protein-Protein Docking Benchmark. The model performs very satisfactorily in terms of speed and accuracy and its results are promising for systematic investigations both on the activation process of tyrosine kinases and other families, and in relation to protein-protein interaction mechanisms.