High-throughput Binding Affinity Calculations at Extreme Scales

Resistance to chemotherapy and molecularly targeted therapies is a major factor in limiting the effectiveness of cancer treatment. In many cases, resistance can be linked to genetic changes in target proteins, either pre-existing or evolutionarily selected during treatment. Key to overcoming this challenge is an understanding of the molecular determinants of drug binding. Using multi-stage pipelines of molecular simulations we can gain insights into the binding free energy and the residence time of a ligand, which can inform both stratified and personal treatment regimes and drug development. To support the scalable, adaptive and automated calculation of the binding free energy on high-performance computing resources, we introduce the High- throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block approach in order to attain both workflow flexibility and performance. We demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage binding affinity calculation pipelines. This permits a rapid time-to-solution that is essentially invariant of the calculation protocol, size of candidate ligands and number of ensemble simulations. As such, HTBAC advances the state of the art of binding affinity calculations and protocols

Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS

GROMACS is a widely used package for biomolecular simulation, and over the last two decades it has evolved from small-scale efficiency to advanced heterogeneous acceleration and multi-level parallelism targeting some of the largest supercomputers in the world. Here, we describe some of the ways we have been able to realize this through the use of parallelization on all levels, combined with a constant focus on absolute performance. Release 4.6 of GROMACS uses SIMD acceleration on a wide range of architectures, GPU offloading acceleration, and both OpenMP and MPI parallelism within and between nodes, respectively. The recent work on acceleration made it necessary to revisit the fundamental algorithms of molecular simulation, including the concept of neighborsearching, and we discuss the present and future challenges we see for exascale simulation - in particular a very fine-grained task parallelism. We also discuss the software management, code peer review and continuous integration testing required for a project of this complexity.Comment: EASC 2014 conference proceedin

Synapse: Synthetic Application Profiler and Emulator

We introduce Synapse motivated by the needs to estimate and emulate workload execution characteristics on high-performance and distributed heterogeneous resources. Synapse has a platform independent application profiler, and the ability to emulate profiled workloads on a variety of heterogeneous resources. Synapse is used as a proxy application (or "representative application") for real workloads, with the added advantage that it can be tuned at arbitrary levels of granularity in ways that are simply not possible using real applications. Experiments show that automated profiling using Synapse represents application characteristics with high fidelity. Emulation using Synapse can reproduce the application behavior in the original runtime environment, as well as reproducing properties when used in a different run-time environments

A General Spatio-Temporal Clustering-Based Non-local Formulation for Multiscale Modeling of Compartmentalized Reservoirs

Representing the reservoir as a network of discrete compartments with neighbor and non-neighbor connections is a fast, yet accurate method for analyzing oil and gas reservoirs. Automatic and rapid detection of coarse-scale compartments with distinct static and dynamic properties is an integral part of such high-level reservoir analysis. In this work, we present a hybrid framework specific to reservoir analysis for an automatic detection of clusters in space using spatial and temporal field data, coupled with a physics-based multiscale modeling approach. In this work a novel hybrid approach is presented in which we couple a physics-based non-local modeling framework with data-driven clustering techniques to provide a fast and accurate multiscale modeling of compartmentalized reservoirs. This research also adds to the literature by presenting a comprehensive work on spatio-temporal clustering for reservoir studies applications that well considers the clustering complexities, the intrinsic sparse and noisy nature of the data, and the interpretability of the outcome. Keywords: Artificial Intelligence; Machine Learning; Spatio-Temporal Clustering; Physics-Based Data-Driven Formulation; Multiscale Modelin

A Bayesian Consistent Dual Ensemble Kalman Filter for State-Parameter Estimation in Subsurface Hydrology

Ensemble Kalman filtering (EnKF) is an efficient approach to addressing uncertainties in subsurface groundwater models. The EnKF sequentially integrates field data into simulation models to obtain a better characterization of the model's state and parameters. These are generally estimated following joint and dual filtering strategies, in which, at each assimilation cycle, a forecast step by the model is followed by an update step with incoming observations. The Joint-EnKF directly updates the augmented state-parameter vector while the Dual-EnKF employs two separate filters, first estimating the parameters and then estimating the state based on the updated parameters. In this paper, we reverse the order of the forecast-update steps following the one-step-ahead (OSA) smoothing formulation of the Bayesian filtering problem, based on which we propose a new dual EnKF scheme, the Dual-EnKF$_{\rm OSA}$. Compared to the Dual-EnKF, this introduces a new update step to the state in a fully consistent Bayesian framework, which is shown to enhance the performance of the dual filtering approach without any significant increase in the computational cost. Numerical experiments are conducted with a two-dimensional synthetic groundwater aquifer model to assess the performance and robustness of the proposed Dual-EnKF$_{\rm OSA}$, and to evaluate its results against those of the Joint- and Dual-EnKFs. The proposed scheme is able to successfully recover both the hydraulic head and the aquifer conductivity, further providing reliable estimates of their uncertainties. Compared with the standard Joint- and Dual-EnKFs, the proposed scheme is found more robust to different assimilation settings, such as the spatial and temporal distribution of the observations, and the level of noise in the data. Based on our experimental setups, it yields up to 25% more accurate state and parameters estimates