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Atomistic Protein Folding Simulations on the Submillisecond Timescale Using Worldwide Distributed Computing. Qing Lu CMSC 838 Presentation. Overview. Overview of talk Motivation Challenge Methods Ensemble Dynamics Folding@Home Evaluation Observations. Motivation.

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Atomistic Protein Folding Simulations on the Submillisecond Timescale Using Worldwide Distributed Computing

Qing Lu

CMSC 838 Presentation

overview
Overview
  • Overview of talk
    • Motivation
    • Challenge
    • Methods
      • Ensemble Dynamics
      • Folding@Home
    • Evaluation
    • Observations

CMSC 838T – Presentation

motivation
Motivation
  • Atomistic simulation of protein folding
    • understand dynamics of folding
    • real-time folding in full atomic detail
    • large-scale parallelization methods
  • Benefits
    • protein folding & disease
      • protein self-assemble to function
      • proteins misfold  diseases
    • nanotechnology
      • nanomachines
      • self-assemble on the nanoscale

CMSC 838T – Presentation

challenge
Challenge
  • Difficulties
    • limited by current computational techniques
      • fastest folding in microseconds
      • one CPU: 1ns/day, 30 years
      • 10,000 fold computational gap
        • 1,000 CPUs, 1 microsecond / day
    • traditional parallelization scheme
      • hard to scale to a large amount of processors
      • extremely fast communication
      • complexity of coordination
      • expensive supercomputers
        • cost
        • time-sharing

CMSC 838T – Presentation

method
Method
  • ensemble dynamics
    • a new simulation algorithm
    • parallel simulation
  • Folding@Home
    • heterogeneous network, Internet
    • large-scale distributed platform

CMSC 838T – Presentation

simulation of dynamics
Simulation of Dynamics
  • free energy barrier
    • progress from one state to another: transition
    • thermal fluctuations to push system over free energy barrier
  • previous approaches: sampling
    • maybe stuck in meta-stable free energy minima
    • expensive computational cost of sampling

CMSC 838T – Presentation

ensemble dynamics
Ensemble Dynamics
  • application scenario
    • waiting time of transitions dominates total time
    • protein folding
      • transition: free energy barrier crossing
    • coupled simulations: transition coupling
  • Algorithm
    • M independent simulations from a initial condition
    • first simulation to cross free energy barrier
      • M times less to cross barrier than average time
    • restart M simulations with the new location after transition
  • Near linear speed up in #processors
    • exponential kinetics: f(t) = 1 – exp(-k t)
    • If k * t is small, f(t) = k * t
    • M simulations  M * f(t) = M * k * t folding events

CMSC 838T – Presentation

limitations
Limitations
  • barrier crossing probability
    • exponential assumptions
  • correct transition detection
    • transition: free energy barrier crossing
    • a large variance in energy: threshold
    • correct detection is not guaranteed
  • multiple possible transition
    • not addressed
    • selection of the first transition

CMSC 838T – Presentation

distributed computing
Distributed Computing
  • Distributed simulations
    • M processors for each run
    • simulate folding in atomic detail on each processor
    • restart once a crossing barrier event occurs
  • Implementation: Folding@Home
    • worldwide distributed computing: Internet
    • started in October 2000
      • more than 200,000 participants
      • 10,000 CPU-years in the first 12 months

CMSC 838T – Presentation

folding@home
Folding@Home

CMSC 838T – Presentation

folding@home1
Folding@Home
  • client-server architecture
    • server assign jobs(work unit) to client
    • client sends back results after computation
    • ~100K data transfer between client and server
  • why is ensemble dynamics good for Folding@Home?
    • CPU intensive job: a few hours, often days
    • connection speed: modem, good enough
    • suitable for Folding@Home

CMSC 838T – Presentation

other@home work
Other@Home Work
  • SETI@Home
    • search for intelligent life outside Earth
    • data analysis of signals
  • FightAids@Home
    • find drug therapy for HIV
    • how drugs interact with various HIV virus mutations
  • distributed projects
    • Divide-and-Conquer
    • CPU intensive jobs
    • small pieces of data(kilobytes) transfer
    • communication not a major concern

CMSC 838T – Presentation

evaluation
Evaluation
  • Folding@Home
    • based on Tinker molecular dynamics code
    • voluntary participants worldwide, over 400,000 CPUs
  • simulate folding and unfolding
    • folding rates
    • simulations on small proteins

CMSC 838T – Presentation

folding rates
Folding Rates

CMSC 838T – Presentation

folding unfolding
Folding & Unfolding

CMSC 838T – Presentation

observations
Observations
  • Sampling
    • too expensive to run for a long timescales
    • waste too much time lingering in local energy minima
  • Ensemble dynamics
    • speed up simulations of dynamics
    • biological meaning of simulations results?
    • results on large protein folding?
    • limitations: correct transition detection, transition probability
  • Folding@Home
    • cheap way to achieve super computation power
    • huge distributed computing platform: over 400,000 CPUs
    • an efficient approach for CPU intensive job
  • Complexity of problems and size of data increase rapidly
    • find better algorithm is preferable to buying supercomputers

CMSC 838T – Presentation