The video at left accompanies a paper by the Lillian Chong Group that was recently published in Nature Communications - "Large enhancements of response times of a protein conformational switch by computational design." This displays a molecular simulation of the switching process for a protein-based calcium sensor, with music written and performed by graduate student Alex DeGrave. Computational resources were provided by the Center for Research Computing.
Chemistry professor Lillian Chong collaborates on WESTPA software to intensify molecular simulation
On a bright winter afternoon in the Pitt Writing Center, Lillian Chong, Associate Professor in Chemistry, talks to a full house of students – some from Chemistry, some from English – a crowd that customarily doesn’t intermingle. Chong, founder of Pitt’s Creative Science Writing Program, is leading a program on science and creativity along with Pitt English Instructor and award-winning poet, Sam Pittman.
“Science is creative,” Chong explains to the class. “Science and writing can reinforce each other.”
On a screen behind her a simulated pair of wriggling protein molecules coyly approach each other, then back away, while students work on poems describing molecular level emotions.
Science and writing combine two of Chong’s passions. She works at the forefront of expanding the possibilities of dynamic simulations like those wriggling protein molecules. Recipient of numerous awards – including an NSF CAREER Award and Pitt’s Tina and David Bellet Teaching Excellence Award – Chong develops tools powerful enough to create biomolecular simulations that model the full compass of critical biological events.
Despite the existence of hardware capable of massive computation, Chong, a Pitt CRC collaborator who serves on the Center’s Advisory Committee, points out that hardware advances alone are not sufficient for computer simulations of biological systems. For example, simulations of relatively small proteins have required expensive, specialized supercomputers to reach timescales of just milliseconds. Many biological processes occur on much longer timescales. Simulating the emergence of rare events such as protein folding requires more than state-of-the-art hardware.
Chong is exploring another approach. Along with Professor Daniel Zuckerman at Oregon Health & Science University, Chong led the development of an open-source interoperable software package with fancy algorithms for enhancing the efficiency of creating and analyzing simulations, known as WESTPA (Weighted Ensemble Simulation Toolkit with Parallelization and Analysis, with a nod to Western Pennsylvania). Chong and Zuckerman initially described the software in a 2015 publication in the Journal of Chemical Theory and Computation.
At the core of WESTPA is a weighted ensemble path sampling algorithm. Essentially, the weighted ensemble algorithm enhances modelling rare events at any level of detail ranging from atomic to cellular and beyond by focusing on sampling transitional pathways, rather than already known stable states. During simulations, existing known pathways are pruned away to focus computation power on underexplored regions. WESTPA focuses on the mechanisms of transitions, creating multiple simulations on multiple paths to reveal the most likely paths and the events affecting the rates and outcomes of transitions.
WESTPA is an attractive tool. It is primarily written in Python, an accessible yet powerful computer programming language, and can be used on any computing resource including typical academic clusters and supercomputers. It interfaces with any stochastic sampling engine. Chong, Zuckerman, and Jim Faeder (Pitt Associate Professor of Computational and Systems Biology) have been awarded a four-year NIH RO1 grant for the continued development and maintenance of WESTPA, including enhancing its interoperability and scaling.
Pitt CRC collaborates with the WESTPA team on a key aim of the grant – improving all aspects of the user experience, including simplifying the installation process, as well as providing detailed tutorials, how-to documentation on writing custom applications, and user support to track performance issues.
Kim Wong, Pitt CRC consultant, collaborates in improving the installation procedure and tutorial examples. In addition to supporting code development for WESTPA, Pitt CRC also hosts and maintains computational hardware specially configured to support simulations using the WESTPA framework.
WESTPA can expand its capability across thousands of processors. To help accommodate that volume of computation, funds from the grant were provided to Pitt CRC to expand its graphics processing unit (GPU) nodes. Based on technology originally developed for video games, GPUs accelerate simulations by an order of magnitude beyond traditional computing that uses central processing units.
The new nodes are available to the larger university community; in return the WESTPA project group is granted priority access to all hardware within the Center’s computing arsenal, including the contributed GPU nodes.
“Adding GPUs is a game changer,” Chong says. “With GPUs, we can run simulations on the microsecond timescale in one to two weeks. Coupled with WESTPA, the resulting weighted ensemble simulations can reach the seconds timescale, which is relevant to the action of drug molecules and has not been attainable using standard simulations on even the most sophisticated hardware.”
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