Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Monday Speaker Abstracts

From High-resolution Protein Structures to Information About Functional Dynamics Therese Malliavin . CNRS/Institut Pasteur, Paris, France. High-resolution protein structures give important information on their function. Nevertheless, the discrete picture of conformational space provided by these structures do not permit to infer a complete vision of the protein functional dynamics. Besides, the enhanced sampling approaches allow a more rapid exploration of the conformational space and thus a better predictive power on the aspects of functional dynamics. Here, we will describe the application of such an approach to several proteins playing a significant biological role. In the context of antibiotics resistance, VanA catalyzes the formation of D-Ala-D-Lac instead of the vancomycin target D-Ala-D-Ala. This reaction requires the opening of the so-called "omega- loop". Enhanced sampling coupled to clustering and graphs building provide a coarse-grained pattern of this opening (Duclert-Savatier et al, 2016). The toxin adenyl cyclase AC from Bordetella pertussis is activated by calmodulin. An high- resolution crystallographic structure is available for activated AC, whereas the inactive state of AC has not been up to now, amenable to high-resolution structural studies. The development of enhanced sampling approaches (Cortes-Ciriano et al, 2015) coupled to an analysis of the biophysical measurements on inactive AC, permits to propose series of protein conformations in agreement with the experimental knowledge on AC. The histidine kinase CpxA belongs to a two-component system, which serves in Escherichia coli to couple environmental stimuli to adaptive responses. The stimuli transmission is performed via conformational transitions of the HAMP and DHp domains, for which various models are available. A combination of molecular dynamics simulations (Martinez et al, 2016), enhanced sampling approaches and fitting to experimental data made possible to probe the relevance of these models. Cortes-Ciriano, Bouvier, Nilges, Maragliano, Malliavin. JCTC 11, 2015. Duclert-Savatier, Bouvier, Nilges, Malliavin. JCIM 56, 2016. Martinez, Duclert-Savatier, Betton, Alzari, Nilges, Malliavin. Biopolymers 105, 2016.

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