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.