Path Similarity Analysis: a Method for Quantifying Macromolecular Pathways

Diverse classes of proteins function through large-scale conformational changes; sophisticated enhanced sampling methods have been proposed to generate these macromolecular transition paths. As such paths are curves in a high-dimensional space, they have been difficult to compare quantitatively, a prerequisite to, for instance, assess the quality of different sampling algorithms. The Path Similarity Analysis (PSA) approach alleviates these difficulties by utilizing the full information in 3N-dimensional trajectories in configuration space. PSA employs the Hausdorff or Fr\'echet path metrics---adopted from computational geometry---enabling us to quantify path (dis)similarity, while the new concept of a Hausdorff-pair map permits the extraction of atomic-scale determinants responsible for path differences. Combined with clustering techniques, PSA facilitates the comparison of many paths, including collections of transition ensembles. We use the closed-to-open transition of the enzyme adenylate kinase (AdK)---a commonly used testbed for the assessment enhanced sampling algorithms---to examine multiple microsecond equilibrium molecular dynamics (MD) transitions of AdK in its substrate-free form alongside transition ensembles from the MD-based dynamic importance sampling (DIMS-MD) and targeted MD (TMD) methods, and a geometrical targeting algorithm (FRODA). A Hausdorff pairs analysis of these ensembles revealed, for instance, that differences in DIMS-MD and FRODA paths were mediated by a set of conserved salt bridges whose charge-charge interactions are fully modeled in DIMS-MD but not in FRODA. We also demonstrate how existing trajectory analysis methods relying on pre-defined collective variables, such as native contacts or geometric quantities, can be used synergistically with PSA, as well as the application of PSA to more complex systems such as membrane transporter proteins.Comment: 9 figures, 3 tables in the main manuscript; supplementary information includes 7 texts (S1 Text - S7 Text) and 11 figures (S1 Fig - S11 Fig) (also available from journal site

Bond-Order Time Series Analysis for Detecting Reaction Events in Ab Initio Molecular Dynamics Simulations.

Ab initio molecular dynamics is able to predict novel reaction mechanisms by directly observing the individual reaction events that occur in simulation trajectories. In this article, we describe an approach for detecting reaction events from simulation trajectories using a physically motivated model based on time series analysis of ab initio bond orders. We found that applying a threshold to the bond order was insufficient for accurate detection, whereas peak finding on the first time derivative resulted in significantly improved accuracy. The model is trained on a reference set of reaction events representing the ideal result given unlimited computing resources. Our study includes two model systems: a heptanylium carbocation that undergoes hydride shifts and an unsaturated iron carbonyl cluster that features CO ligand migration and bridging behavior. The results indicate a high level of promise for this analysis approach to be used in mechanistic analysis of reactive AIMD simulations more generally

Scalable Approach to Uncertainty Quantification and Robust Design of Interconnected Dynamical Systems

Development of robust dynamical systems and networks such as autonomous aircraft systems capable of accomplishing complex missions faces challenges due to the dynamically evolving uncertainties coming from model uncertainties, necessity to operate in a hostile cluttered urban environment, and the distributed and dynamic nature of the communication and computation resources. Model-based robust design is difficult because of the complexity of the hybrid dynamic models including continuous vehicle dynamics, the discrete models of computations and communications, and the size of the problem. We will overview recent advances in methodology and tools to model, analyze, and design robust autonomous aerospace systems operating in uncertain environment, with stress on efficient uncertainty quantification and robust design using the case studies of the mission including model-based target tracking and search, and trajectory planning in uncertain urban environment. To show that the methodology is generally applicable to uncertain dynamical systems, we will also show examples of application of the new methods to efficient uncertainty quantification of energy usage in buildings, and stability assessment of interconnected power networks