Conformational Ensembles from Experimental Data and Computer Simulations

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Conformational Ensembles from Experimental Data
and Computer Simulations Poster Abstracts
72
39-POS Board 39
A Simulation-Guided Method to Select Optimal DEER Experiments to Refine Highly
Flexible Conformational Ensembles
Jennifer M. Hays1, Marissa Keiber2, Linda Columbus2, Peter M. Kasson3,1.
1University of Virginia, Charlottesville, VA, USA, 3University of Virginia, Charlottesville, VA,
USA.2University of Virginia, Charlottesville, VA, USA,
Determining the structural basis of flexible molecular recognition is experimentally challenging
because many techniques that capture multiple conformational populations provide sparse rather
than complete data on the conformational ensemble. Selecting a set of optimal experiments to
best refine the conformational ensemble therefore remains an important challenge. The binding
of Opa Neisserial virulence protein to its human host receptor (CEACAM) exemplifies these
flexible recognition processes. Although Opa has long loops that have been shown by NMR to
be loosely structured, these same loops still bind CEACAM with high affinity. In order to refine
the Opa-CEACAM conformational ensemble, we have developed a model-free, information-
theoretic approach for guiding double electron-electron resonance (DEER) experiments that 1)
uses a mutual information distance metric to rank pairs of residues based on how well they refine
a conformational ensemble and 2) identifies a set of highly informative pairs that perform well
under this metric. Specifically, we utilize the data from initial ensemble simulations of Opa60 to
identify a set of maximally-informative and minimally-redundant (mRMR) pairs, measure the
distance distributions of those pairs using DEER, incorporate the experimental distributions into
restrained-ensemble MD simulations, and demonstrate that the set of high-scoring mRMR pairs
better reduces the conformational search space than a set of experimentalist-selected pairs. This
systematic approach provides a way to both efficiently refine flexible receptor-ligand complexes
and help elucidate fundamental physical principles of receptor-ligand binding.