Intelligent resolution: Integrating Cryo-EM with AI-driven multi-resolution simulations to observe the severe acute respiratory syndrome coronavirus-2 replication-transcription machinery in action

Anda Trifan, Defne Gorgun, Michael Salim, Zongyi Li, Alexander Brace, Maxim Zvyagin, Heng Ma, Austin Clyde, David Clark, David J. Hardy, Tom Burnley, Lei Huang, John McCalpin, Murali Emani, Hyenseung Yoo, Junqi Yin, Aristeidis Tsaris, Vishal Subbiah, Tanveer Raza, Jessica LiuNoah Trebesch, Geoffrey Wells, Venkatesh Mysore, Thomas Gibbs, James Phillips, S. Chakra Chennubhotla, Ian Foster, Rick Stevens, Anima Anandkumar, Venkatram Vishwanath, John E. Stone, Emad Tajkhorshid, Sarah A. Harris, Arvind Ramanathan

Research output: Contribution to journalArticlepeer-review

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication transcription complex (RTC) is a multi-domain protein responsible for replicating and transcribing the viral mRNA inside a human cell. Attacking RTC function with pharmaceutical compounds is a pathway to treating COVID-19. Conventional tools, e.g. cryo-electron microscopy and all-atom molecular dynamics (AAMD), do not provide sufficiently high resolution or timescale to capture important dynamics of this molecular machine. Consequently, we develop an innovative workflow that bridges the gap between these resolutions, using mesoscale fluctuating finite element analysis (FFEA) continuum simulations and a hierarchy of AI-methods that continually learn and infer features for maintaining consistency between AAMD and FFEA simulations. We leverage a multi-site distributed workflow manager to orchestrate AI, FFEA, and AAMD jobs, providing optimal resource utilization across HPC centers. Our study provides unprecedented access to study the SARS-CoV-2 RTC machinery, while providing general capability for AI-enabled multi-resolution simulations at scale.

Original languageEnglish (US)
Pages (from-to)603-623
Number of pages21
JournalInternational Journal of High Performance Computing Applications
Volume36
Issue number5-6
Early online dateAug 5 2022
DOIs
StatePublished - Nov 2022

Keywords

  • High performance computing
  • Multi-resolution simulations
  • artificial intelligence
  • coronavirus 2019
  • severe acute respiratory syndrome coronavirus-2

ASJC Scopus subject areas

  • Theoretical Computer Science
  • Software
  • Hardware and Architecture

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