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Modeling protein conformational transitions by a combination of coarse-grained normal mode analysis and robotics-inspired methods

Ibrahim Al Bluwi 1 Marc Vaisset 2 Thierry Simeon 1 Juan Cortés 1
1 LAAS-RIS - Équipe Robotique et InteractionS
LAAS - Laboratoire d'analyse et d'architecture des systèmes
2 LAAS-IDEA - Service Informatique : Développement, Exploitation et Assistance
LAAS - Laboratoire d'analyse et d'architecture des systèmes
Abstract : Background:Obtaining atomic-scale information about large-amplitude conformational transitions in proteins is achallenging problem for both experimental and computational methods. Such information is, however, importantfor understanding the mechanisms of interaction of many proteins.Methods:This paper presents a computationally efficient approach, combining methods originating from roboticsand computational biophysics, to model protein conformational transitions. The ability of normal mode analysis topredict directions of collective, large-amplitude motions is applied to bias the conformational explorationperformed by a motion planning algorithm. To reduce the dimension of the problem, normal modes arecomputed for a coarse-grained elastic network model built on short fragments of three residues. Nevertheless, thevalidity of intermediate conformations is checked using the all-atom model, which is accurately reconstructed fromthe coarse-grained one using closed-form inverse kinematics.Results:Tests on a set of ten proteins demonstrate the ability of the method to model conformational transitionsof proteins within a few hours of computing time on a single processor. These results also show that thecomputing time scales linearly with the protein size, independently of the protein topology. Further experimentson adenylate kinase show that main features of the transition between the open and closed conformations of thisprotein are well captured in the computed path.Conclusions:The proposed method enables the simulation of large-amplitude conformational transitions inproteins using very few computational resources. The resulting paths are a first approximation that can directlyprovide important information on the molecular mechanisms involved in the conformational transition. Thisapproximation can be subsequently refined and analyzed using state-of-the-art energy models and molecularmodeling methods.
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Ibrahim Al Bluwi, Marc Vaisset, Thierry Simeon, Juan Cortés. Modeling protein conformational transitions by a combination of coarse-grained normal mode analysis and robotics-inspired methods. BMC Structural Biology, BioMed Central, 2013, 13 (Suppl 1), pp.S2. ⟨10.1186/1472-6807-13-S1-S2⟩. ⟨hal-01980925⟩

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