Scientists Create 3D Model of Intrinsically Disordered Protein with Titan Supercomputer, Spallation Neutron Source

October 7, 2019

OAK RIDGE, Tenn., Oct. 7, 2019— Using the Titan supercomputer and the Spallation Neutron Source at the Department of Energy’s Oak Ridge National Laboratory, scientists have created the most accurate 3D model yet of an intrinsically disordered protein, revealing the ensemble of its atomic-level structures.

As its name indicates, an IDP does not adopt an ordered, static structure like other proteins; instead, it’s flexible and can adopt multiple 3D structures. This lack of a unique structure is necessary for the IDP’s biological function but makes it technically challenging to study. IDPs may be a whole protein or a domain of an otherwise structured protein, and they make up a large portion of human, microbe, and plant proteins.

Loukas Petridis, a staff scientist at the Center for Molecular Biophysics at ORNL, has directed a team of researchers to a new way to create accurate physical models of such flexible biosystems, which can lead to a better understanding of their biological functions. Over the past three years, the team has combined neutron scattering experiments with enhanced sampling molecular dynamics (MD) simulations so computationally demanding that they required the processing power of Titan, the recently decommissioned 27-petaflop Cray XK7 at the Oak Ridge Leadership Computing Facility, a DOE Office of Science User Facility at ORNL.

“To study these IDPs is quite difficult, from both perspectives of experiments and modeling,” said Utsab Shrestha, the lead author of the team’s paper, recently published in the Proceedings of the National Academy of Sciences. “We not only thought about it from experiment or simulation alone, we planned in a way that we would synergize both of these approaches—combine them in a way that we could get more precise information on IDPs. Specifically, simulations helped us to generate an accurate ensemble of IDP at atomic resolution, which is difficult to determine from experiments alone.”

Typically, researchers conduct experiments such as small-angle neutron scattering, small-angle x-ray scattering, or nuclear magnetic resonance to probe flexible biological systems. However, these methods do not provide a detailed atomic-level picture of an IDP’s 3D structures, known as its configurational ensemble. Furthermore, they can only produce ensemble-averaged data, rather than the specific underlying protein structure configurations. Scientists have also performed computer simulations of IDP and compared them with such experiments, hoping to get the same results in order to verify the accuracy of their models.

“But they end up not agreeing with the experiments,” Petridis said. “And because of the discrepancy between the simulations and the experiments, they have to reweight the simulations—they have to adjust the simulation results to make them match the experiments, which is frustrating. That was the state of the art until our work.”

Computer MD simulations conducted by Shrestha used enhanced sampling methods that succeeded in matching not only neutron scattering experiments—conducted by Viswanathan Gurumoorthy and his colleagues at SNS, a DOE Office of Science User Facility at ORNL—but also previously published NMR data. These MD simulations use physics to determine how proteins move. Key to the team’s success was running many MD simulations in parallel on Titan, allowing the simulations to communicate with each other and exchange information.

“This is very important because it allows the simulation to sample a larger configurational space, explore more of the three-dimensional structures in a more efficient way,” Petridis said. “That’s why this enhanced-sampling MD can produce results that the normal MD simulation cannot. We’d have to run a normal MD simulation for years to obtain the same results.”

The IDP that the team chose to study is the N-terminal domain of c-Src kinase, which is a major signaling protein in humans. Mutations in this complex protein have been correlated with cancer, which also makes it an important drug target. While mapping this previously murky domain, the scientists were able to discover new information about its 3D structures that previous methods had not shown. For example, although it is largely disordered, this protein forms transient ordered structures, such as helices.

“The combination of neutron scattering experiments and simulation is very powerful,” Petridis said. “Validation of the simulations by comparison to neutron scattering experiments is essential to have confidence in the simulation results. The validated simulations can then provide detailed information that is not directly obtained by experiments.”

The detailed computer model of the IDP’s 3D structure ensemble opens the door to more experimentation. For example, scientists could simulate the effect of phosphorylation (the addition of a phosphate group to the protein that can regulate the protein’s function) to see what structural changes take place in c-Src kinase that could influence its function. The role of mutations could also be examined: If a researcher changes an amino acid in the chain, how does this affect the structure or the ensemble of structures?

“There are a lot of unanswered questions for c-Src kinase in particular that could be answered in terms of the interactions with other partners—the effect of phosphorylation, the effect of mutations,” Petridis said.

Beyond the potential scientific uses for the model itself, Petridis sees opportunities to apply the use of high-performance computing for running enhanced sampling MD to study the structures of many other important IDPs, which could give insight to their function. And more broadly, the team wants to develop simulation technologies that can reproduce small-angle neutron scattering profiles of even more complex biological systems.

“We don’t want to investigate only the disordered proteins—we want to have much bigger systems that contain ordered and disordered domains that may be interacting with membranes or DNA,” Petridis said. “Neutron scattering is, in my view, the best experimental technique to probe these multi-component systems—for example, a protein that interacts with a membrane or a protein that interacts with DNA. But, still, neutron scattering needs the accurate simulations to better interpret the data.”

Coauthors of this study include Utsab R. Shrestha, Puneet Juneja, Qiu Zhang, Viswanathan Gurumoorthy, Jose M. Borreguero, Volker Urban, Xiaolin Cheng, Sai Venkatesh Pingali, Jeremy C. Smith, Hugh M. O’Neill, and Loukas Petridis. Support for this project came from ORNL’s Laboratory Directed Research and Development Program and from DOE’s Office of Science. In addition to using the OLCF’s Titan supercomputer and Spallation Neutron Source, the team performed research at the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility at Lawrence Berkeley National Laboratory.

UT-Battelle LLC manages Oak Ridge National Laboratory for DOE’s Office of Science, the single largest supporter of basic research in the physical sciences in the United States. DOE’s Office of Science is working to address some of the most pressing challenges of our time. For more information, visit https://energy.gov/science.


Source: Oak Ridge National Laboratory 

Subscribe to HPCwire's Weekly Update!

Be the most informed person in the room! Stay ahead of the tech trends with industy updates delivered to you every week!

Simulating Car Crashes with Supercomputers – and Lego

October 18, 2019

It’s an experiment many of us have carried out at home: crashing two Lego creations into each other, bricks flying everywhere. But for the researchers at the General German Automobile Club (ADAC) – which is comparabl Read more…

By Oliver Peckham

NASA Uses Deep Learning to Monitor Solar Weather

October 17, 2019

Solar flares may be best-known as sci-fi MacGuffins, but those flares – and other space weather – can have serious impacts on not only spacecraft and satellites, but also on Earth-based systems such as radio communic Read more…

By Oliver Peckham

Federated Learning Applied to Cancer Research

October 17, 2019

The ability to share and analyze data while protecting patient privacy is giving medical researchers a new tool in their efforts to use what one vendor calls “federated learning” to train models based on diverse data Read more…

By George Leopold

Using AI to Solve One of the Most Prevailing Problems in CFD

October 17, 2019

How can artificial intelligence (AI) and high-performance computing (HPC) solve mesh generation, one of the most commonly referenced problems in computational engineering? A new study has set out to answer this question and create an industry-first AI-mesh application... Read more…

By James Sharpe

NSB 2020 S&E Indicators Dig into Workforce and Education

October 16, 2019

Every two years the National Science Board is required by Congress to issue a report on the state of science and engineering in the U.S. This year, in a departure from past practice, the NSB has divided the 2020 S&E Read more…

By John Russell

AWS Solution Channel

Making High Performance Computing Affordable and Accessible for Small and Medium Businesses with HPC on AWS

High performance computing (HPC) brings a powerful set of tools to a broad range of industries, helping to drive innovation and boost revenue in finance, genomics, oil and gas extraction, and other fields. Read more…

HPE Extreme Performance Solutions

Intel FPGAs: More Than Just an Accelerator Card

FPGA (Field Programmable Gate Array) acceleration cards are not new, as they’ve been commercially available since 1984. Typically, the emphasis around FPGAs has centered on the fact that they’re programmable accelerators, and that they can truly offer workload specific hardware acceleration solutions without requiring custom silicon. Read more…

IBM Accelerated Insights

How Do We Power the New Industrial Revolution?

[Attend the IBM LSF, HPC & AI User Group Meeting at SC19 in Denver on November 19!]

Almost everyone is talking about artificial intelligence (AI). Read more…

What’s New in HPC Research: Rabies, Smog, Robots & More

October 14, 2019

In this bimonthly feature, HPCwire highlights newly published research in the high-performance computing community and related domains. From parallel programming to exascale to quantum computing, the details are here. Read more…

By Oliver Peckham

Using AI to Solve One of the Most Prevailing Problems in CFD

October 17, 2019

How can artificial intelligence (AI) and high-performance computing (HPC) solve mesh generation, one of the most commonly referenced problems in computational engineering? A new study has set out to answer this question and create an industry-first AI-mesh application... Read more…

By James Sharpe

NSB 2020 S&E Indicators Dig into Workforce and Education

October 16, 2019

Every two years the National Science Board is required by Congress to issue a report on the state of science and engineering in the U.S. This year, in a departu Read more…

By John Russell

Crystal Ball Gazing: IBM’s Vision for the Future of Computing

October 14, 2019

Dario Gil, IBM’s relatively new director of research, painted a intriguing portrait of the future of computing along with a rough idea of how IBM thinks we’ Read more…

By John Russell

Summit Simulates Braking – on Mars

October 14, 2019

NASA is planning to send humans to Mars by the 2030s – and landing on the surface will be considerably trickier than landing a rover like Curiosity. To solve Read more…

By Staff report

Trovares Drives Memory-Driven, Property Graph Analytics Strategy with HPE

October 10, 2019

Trovares, a high performance property graph analytics company, has partnered with HPE and its Superdome Flex memory-driven servers on a cybersecurity capability the companies say “routinely” runs near-time workloads on 24TB-capacity systems... Read more…

By Doug Black

Intel, Lenovo Join Forces on HPC Cluster for Flatiron

October 9, 2019

An HPC cluster with deep learning techniques will be used to process petabytes of scientific data as part of workload-intensive projects spanning astrophysics to genomics. AI partners Intel and Lenovo said they are providing... Read more…

By George Leopold

Optimizing Offshore Wind Farms with Supercomputer Simulations

October 9, 2019

Offshore wind farms offer a number of benefits; many of the areas with the strongest winds are located offshore, and siting wind farms offshore ameliorates many of the land use concerns associated with onshore wind farms. Some estimates say that, if leveraged, offshore wind power... Read more…

By Oliver Peckham

Harvard Deploys Cannon, New Lenovo Water-Cooled HPC Cluster

October 9, 2019

Harvard's Faculty of Arts & Sciences Research Computing (FASRC) center announced a refresh of their primary HPC resource. The new cluster, called Cannon after the pioneering American astronomer Annie Jump Cannon, is supplied by Lenovo... Read more…

By Tiffany Trader

Supercomputer-Powered AI Tackles a Key Fusion Energy Challenge

August 7, 2019

Fusion energy is the Holy Grail of the energy world: low-radioactivity, low-waste, zero-carbon, high-output nuclear power that can run on hydrogen or lithium. T Read more…

By Oliver Peckham

DARPA Looks to Propel Parallelism

September 4, 2019

As Moore’s law runs out of steam, new programming approaches are being pursued with the goal of greater hardware performance with less coding. The Defense Advanced Projects Research Agency is launching a new programming effort aimed at leveraging the benefits of massive distributed parallelism with less sweat. Read more…

By George Leopold

Cray Wins NNSA-Livermore ‘El Capitan’ Exascale Contract

August 13, 2019

Cray has won the bid to build the first exascale supercomputer for the National Nuclear Security Administration (NNSA) and Lawrence Livermore National Laborator Read more…

By Tiffany Trader

AMD Launches Epyc Rome, First 7nm CPU

August 8, 2019

From a gala event at the Palace of Fine Arts in San Francisco yesterday (Aug. 7), AMD launched its second-generation Epyc Rome x86 chips, based on its 7nm proce Read more…

By Tiffany Trader

Ayar Labs to Demo Photonics Chiplet in FPGA Package at Hot Chips

August 19, 2019

Silicon startup Ayar Labs continues to gain momentum with its DARPA-backed optical chiplet technology that puts advanced electronics and optics on the same chip Read more…

By Tiffany Trader

Using AI to Solve One of the Most Prevailing Problems in CFD

October 17, 2019

How can artificial intelligence (AI) and high-performance computing (HPC) solve mesh generation, one of the most commonly referenced problems in computational engineering? A new study has set out to answer this question and create an industry-first AI-mesh application... Read more…

By James Sharpe

D-Wave’s Path to 5000 Qubits; Google’s Quantum Supremacy Claim

September 24, 2019

On the heels of IBM’s quantum news last week come two more quantum items. D-Wave Systems today announced the name of its forthcoming 5000-qubit system, Advantage (yes the name choice isn’t serendipity), at its user conference being held this week in Newport, RI. Read more…

By John Russell

Chinese Company Sugon Placed on US ‘Entity List’ After Strong Showing at International Supercomputing Conference

June 26, 2019

After more than a decade of advancing its supercomputing prowess, operating the world’s most powerful supercomputer from June 2013 to June 2018, China is keep Read more…

By Tiffany Trader

Leading Solution Providers

ISC 2019 Virtual Booth Video Tour

CRAY
CRAY
DDN
DDN
DELL EMC
DELL EMC
GOOGLE
GOOGLE
ONE STOP SYSTEMS
ONE STOP SYSTEMS
PANASAS
PANASAS
VERNE GLOBAL
VERNE GLOBAL

A Behind-the-Scenes Look at the Hardware That Powered the Black Hole Image

June 24, 2019

Two months ago, the first-ever image of a black hole took the internet by storm. A team of scientists took years to produce and verify the striking image – an Read more…

By Oliver Peckham

Intel Confirms Retreat on Omni-Path

August 1, 2019

Intel Corp.’s plans to make a big splash in the network fabric market for linking HPC and other workloads has apparently belly-flopped. The chipmaker confirmed to us the outlines of an earlier report by the website CRN that it has jettisoned plans for a second-generation version of its Omni-Path interconnect... Read more…

By Staff report

Crystal Ball Gazing: IBM’s Vision for the Future of Computing

October 14, 2019

Dario Gil, IBM’s relatively new director of research, painted a intriguing portrait of the future of computing along with a rough idea of how IBM thinks we’ Read more…

By John Russell

Kubernetes, Containers and HPC

September 19, 2019

Software containers and Kubernetes are important tools for building, deploying, running and managing modern enterprise applications at scale and delivering enterprise software faster and more reliably to the end user — while using resources more efficiently and reducing costs. Read more…

By Daniel Gruber, Burak Yenier and Wolfgang Gentzsch, UberCloud

Intel Debuts Pohoiki Beach, Its 8M Neuron Neuromorphic Development System

July 17, 2019

Neuromorphic computing has received less fanfare of late than quantum computing whose mystery has captured public attention and which seems to have generated mo Read more…

By John Russell

Rise of NIH’s Biowulf Mirrors the Rise of Computational Biology

July 29, 2019

The story of NIH’s supercomputer Biowulf is fascinating, important, and in many ways representative of the transformation of life sciences and biomedical res Read more…

By John Russell

Quantum Bits: Neven’s Law (Who Asked for That), D-Wave’s Steady Push, IBM’s Li-O2- Simulation

July 3, 2019

Quantum computing’s (QC) many-faceted R&D train keeps slogging ahead and recently Japan is taking a leading role. Yesterday D-Wave Systems announced it ha Read more…

By John Russell

With the Help of HPC, Astronomers Prepare to Deflect a Real Asteroid

September 26, 2019

For years, NASA has been running simulations of asteroid impacts to understand the risks (and likelihoods) of asteroids colliding with Earth. Now, NASA and the European Space Agency (ESA) are preparing for the next, crucial step in planetary defense against asteroid impacts: physically deflecting a real asteroid. Read more…

By Oliver Peckham

  • arrow
  • Click Here for More Headlines
  • arrow
Do NOT follow this link or you will be banned from the site!
Share This