Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

107-POS Board 27 Combining Small Angle X-ray Scattering Experiments with Accelerated Molecular Dynamics Simulations to Determine the Conformational Ensemble of Tri-ubiquitin Chains Jeff Wereszczynski . Illinois Institute of Technology, Chicago, IL, USA. Small angle X-ray scattering (SAXS) has become an increasingly popular structural technique for characterizing the ensemble of solution states of flexible biomolecules. However, data resulting from SAXS is typically noisy and low-dimensional and may therefore be difficult to interpret without additional structural knowledge. In principle, this information can be provided by molecular dynamics (MD) simulation, but conventional MD trajectories rarely sample sufficient phase space to probe the range of structures that contribute to the observed experimental data. Accelerated MD (aMD) can overcome these sampling inadequacies by introducing a bias to the underlying energy landscape that lowers the height of energy barriers and encourages conformational transitions, albeit at the cost of distorting the Boltzmann distribution of states. Here, we present a method for combining the results of aMD simulations with experimental SAXS data to accurately model the relative populations of representative solution states. Scattering states are first identified from aMD trajectories, and their populations are then re-weighted against empirical data through a Bayesian Monte Carlo approach. Special care is taken to avoid ensemble over-fitting by iteratively considering increasing subsets of scattering states along with the associated Akaike Information Criterion, and by reducing experimental data to the Shannon sampling limit. We apply this technique to several ubiquitin trimers and find that aMD trajectories typically outperform conventional MD simulations in both goodness-of-fit and model convergence speed. Furthermore, we observe that different ubiquitin linkages yield distinct ensembles, which points to their unique roles in biological signaling. These methods are being implemented in the “SASSIE” webserver, which aims to provide an easy-to-use modeling interface for interpreting data from scattering experiments.

144