SDSC Supercomputer Modeling Reveals Acrobatics of CRISPR-Cas9 Technology

September 13, 2016

Sept. 13 — A team led by researchers at the University of California San Diego has captured in step-by-step atomic detail the surgical editing of DNA strands by CRISPR-Cas9, the innovative gene-splicing technology that in recent years has transformed the field of genetic engineering.

Simulations performed by the Comet supercomputer at the San Diego Supercomputer Center (SDSC) at UC San Diego describe the “striking plasticity” of CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 and how it identifies, merges, and slices its target DNA strand. What’s more, the findings offer for the first hints at a key role played by the leftover non-target DNA strand, whose part in this biological cast of characters previously was unclear.

The goal of this study — published in the September 8 issue of ACS Central Science, the new flagship journal of the American Chemical Society — is to provide a foundation for the design of other novel, highly accurate genome-splicing technologies that don’t yield the “off-target” DNA breaks currently frustrating the potential of the current CRISPR-Cas9 system, particularly for clinical uses.

“CRISPR-Cas9 is not perfect since it can cause off-target effects or non-selective cleavage of DNA sequences, creating unwanted collateral damage,” said Giulia Palermo, a postdoctoral scholar with the UC San Diego Department of Pharmacology and lead author of the study.

“If we can design a very specific genome editing machinery, we can target the modification of genes controlling several diseases, including rare diseases and brain diseases, that are difficult to cure with available drugs,” added the study’s principal investigator J. Andrew McCammon, the Joseph E. Mayer Chair of Theoretical Chemistry, a Howard Hughes Medical Institute investigator, and Distinguished Professor of Pharmacology, all at UC San Diego.

“The rational design of more specific Cas9s, which are economically and environmentally friendly, and free from ethical issues, is our ultimate goal,” he said.

As its name implies, CRISPR-Cas9 is a dual entity with dual functions. The first consists of a short RNA guide molecule, part of which matches a target DNA sequence; the second is a Cas9 enzyme that recognizes and slices the DNA in a precise spot, whose location or address is post-marked by a nucleotide sequence called a protospacer adjacent motif, or PAM. The result is an RNA-DNA hybrid with a displaced non-target DNA strand.

Dubbed Science magazine’s “breakthrough of the year” in 2015, enthusiastic researchers around the world are just now scratching the surface of CRISPR-Cas9’s potential, with hopes of treating diseases through gene therapy, or driving advances in areas from crop engineering to the production of biofuels. What the technology ideally offers is specificity: the ability to target, edit, and insert new fragments of DNA sequences into the vast genome of the human and other species of animals and plants.

However, this transformative technology – known for the ease with which it can be programmed to cleave specific DNA targets – isn’t without its flaws. Studies have revealed that the RNA guide used to direct the cleaving enzyme to its target can sometimes go astray, landing on other DNA strands with similar but not identical sequences. The result is “off-target” mutations, severely limiting the technology’s vast array of potential applications, particular for human therapy.

Although extensive studies of the CRISPR-Cas9 systems, including X-ray crystallography and cryoelectron microscopy (cryoEM), have revealed detailed views of the system’s structure and biological activity, the dynamics of Cas9 and its step-by-step acrobatics with nucleic acids during its merger and cleavage of DNA have remained fuzzy at best.

To produce a motion picture-like view of this molecular interplay, UC San Diego researchers turned to the Comet supercomputer to perform atomistic molecular dynamics – a method that captures a more complete vision of the myriad shapes and conformations that a target protein molecule may go through – at petascale speeds (one quadrillion arithmetic calculations per second).

“Access to Comet, greatly facilitated by SDSC, was essential to completing this work in a reasonable timeframe,” said McCammon, also an SDSC Fellow and chemistry and biochemistry professor in UC San Diego’s Division of Physical Sciences. “The power of high-performance computing at the petascale-level and atomistic molecular dynamics simulations are needed to obtain key insights and relevant biophysical information that otherwise are inaccessible with currently available experimental techniques.”

The resulting simulations, performed over multi-microsecond timescales, revealed for the first time what the research team called the “remarkable” plasticity of the Cas9 system, and identified key factors underlying the myriad structural changes taking place during the merger and preparation for cleaving of its target DNA strand.

Of particular interest, the researchers were surprised to find that the leftover non-target DNA strand, whose role was generally considered unimportant, is actually a critical player in the system, serving as a type of starter key that triggers the final stage of the process.

“The motion and position of the non-target DNA strand triggers local conformational changes that result in a shift of an active domain site (HNH) of Cas9 towards the cleavage site on the target DNA for catalysis,” said McCammon, recently named the winner of the 2016-17 Joseph O. Hirschfelder Prize in Theoretical Chemistry, awarded by the Theoretical Chemistry Institute at the University of Wisconsin-Madison. “These molecular simulations strongly suggest the presence of non-target DNA as a key factor for the conformational activation of the HNH domain.”

Also participating the study, called “Striking plasticity of CRISPR-Cas9 and key role of non-target DNA, as revealed by molecular simulations”, were: Yinglong Miao, a research specialist with the Howard Hughes Medical Institute at UC San Diego and research scientist with the UC San Diego Department of Pharmacology; Ross C. Walker, associate research professor at SDSC, NVIDA Fellow, and adjunct associate professor in the Department of Chemistry and Biochemistry at UC San Diego; and Martin Jinek, currently an assistant professor at the University of Zurich who first discovered, in Jennifer Doudna’s lab at UC Berkeley, the ability of Cas9 to be programmed with single RNA strands for efficient DNA cleavage.

Funding for the study was provided by the Swiss National Science Foundation, in addition to grants to the McCammon lab from the National Institutes of Health, the National Science Foundation, and Howard Hughes Medical Institute; and research fellowships to Ross Walker from Intel and NVIDIA.

About SDSC

As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s Comet joins the Center’s data-intensive Gordon cluster, and are both part of the National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) program.


Source: SDSC

Subscribe to HPCwire's Weekly Update!

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

Apple Buys DarwinAI Deepening its AI Push According to Report

March 14, 2024

Apple has purchased Canadian AI startup DarwinAI according to a Bloomberg report today. Apparently the deal was done early this year but still hasn’t been publicly announced according to the report. Apple is preparing Read more…

Survey of Rapid Training Methods for Neural Networks

March 14, 2024

Artificial neural networks are computing systems with interconnected layers that process and learn from data. During training, neural networks utilize optimization algorithms to iteratively refine their parameters until Read more…

PASQAL Issues Roadmap to 10,000 Qubits in 2026 and Fault Tolerance in 2028

March 13, 2024

Paris-based PASQAL, a developer of neutral atom-based quantum computers, yesterday issued a roadmap for delivering systems with 10,000 physical qubits in 2026 and full fault-tolerance operation using 128-plus logical qub Read more…

India Is an AI Powerhouse Waiting to Happen, but Challenges Await

March 12, 2024

The Indian government is pushing full speed ahead to make the country an attractive technology base, especially in the hot fields of AI and semiconductors, but ambition and caution have the country at a crossroads.  Read more…

Charles Tahan Exits National Quantum Coordination Office

March 12, 2024

(March 1, 2024) My first official day at the White House Office of Science and Technology Policy (OSTP) was June 15, 2020, during the depths of the COVID-19 lockdown, and with nine-foot riot fences still up around the Wh Read more…

AI Bias In the Spotlight On International Women’s Day

March 11, 2024

What impact does AI bias have on women and girls? What can people do to increase female participation in the AI field? These are some of the questions the tech world is grappling with today in honor of International Wome Read more…

Survey of Rapid Training Methods for Neural Networks

March 14, 2024

Artificial neural networks are computing systems with interconnected layers that process and learn from data. During training, neural networks utilize optimizat Read more…

PASQAL Issues Roadmap to 10,000 Qubits in 2026 and Fault Tolerance in 2028

March 13, 2024

Paris-based PASQAL, a developer of neutral atom-based quantum computers, yesterday issued a roadmap for delivering systems with 10,000 physical qubits in 2026 a Read more…

India Is an AI Powerhouse Waiting to Happen, but Challenges Await

March 12, 2024

The Indian government is pushing full speed ahead to make the country an attractive technology base, especially in the hot fields of AI and semiconductors, but Read more…

Charles Tahan Exits National Quantum Coordination Office

March 12, 2024

(March 1, 2024) My first official day at the White House Office of Science and Technology Policy (OSTP) was June 15, 2020, during the depths of the COVID-19 loc Read more…

AI Bias In the Spotlight On International Women’s Day

March 11, 2024

What impact does AI bias have on women and girls? What can people do to increase female participation in the AI field? These are some of the questions the tech Read more…

Next Euro HPC Chip Coming Next Year Will Be in 2026 EU Exascale System

March 7, 2024

The next supercomputing chip for Europe's homegrown Exascale supercomputer will come next year, according to an updated product roadmap. The 2025-bound Rhea- Read more…

OLCF’s Summit Supercomputer Lives for Another Year with SummitPLUS

March 6, 2024

The giant supercomputer Summit — based at Oak Ridge National Lab’s Leadership Computing Facility (OLCF) —  lives on, at least for one more year supported Read more…

Google, XPRIZE Launch $5M Quantum Application Challenge

March 4, 2024

Google Quantum AI, the XPRIZE Foundation, and the Geneva Science and Diplomacy Anticipator (GESDA) Foundation have announced a 3-year, $5 million global competi Read more…

Alibaba Shuts Down its Quantum Computing Effort

November 30, 2023

In case you missed it, China’s e-commerce giant Alibaba has shut down its quantum computing research effort. It’s not entirely clear what drove the change. Read more…

Nvidia H100: Are 550,000 GPUs Enough for This Year?

August 17, 2023

The GPU Squeeze continues to place a premium on Nvidia H100 GPUs. In a recent Financial Times article, Nvidia reports that it expects to ship 550,000 of its lat Read more…

Nvidia Wins SC23, But Gets Socked by Microsoft’s AI Chip

November 16, 2023

Nvidia was invisible with a very small booth and limited floor presence, but thanks to its sheer AI dominance, it was a winner at the Supercomputing 2023. Nv Read more…

Analyst Panel Says Take the Quantum Computing Plunge Now…

November 27, 2023

Should you start exploring quantum computing? Yes, said a panel of analysts convened at Tabor Communications HPC and AI on Wall Street conference earlier this y Read more…

DoD Takes a Long View of Quantum Computing

December 19, 2023

Given the large sums tied to expensive weapon systems – think $100-million-plus per F-35 fighter – it’s easy to forget the U.S. Department of Defense is a Read more…

Training of 1-Trillion Parameter Scientific AI Begins

November 13, 2023

A US national lab has started training a massive AI brain that could ultimately become the must-have computing resource for scientific researchers. Argonne N Read more…

Shutterstock 1285747942

AMD’s Horsepower-packed MI300X GPU Beats Nvidia’s Upcoming H200

December 7, 2023

AMD and Nvidia are locked in an AI performance battle – much like the gaming GPU performance clash the companies have waged for decades. AMD has claimed it Read more…

Synopsys Eats Ansys: Does HPC Get Indigestion?

February 8, 2024

Recently, it was announced that Synopsys is buying HPC tool developer Ansys. Started in Pittsburgh, Pa., in 1970 as Swanson Analysis Systems, Inc. (SASI) by John Swanson (and eventually renamed), Ansys serves the CAE (Computer Aided Engineering)/multiphysics engineering simulation market. Read more…

Leading Solution Providers

Contributors

Intel’s Server and PC Chip Development Will Blur After 2025

January 15, 2024

Intel's dealing with much more than chip rivals breathing down its neck; it is simultaneously integrating a bevy of new technologies such as chiplets, artificia Read more…

Baidu Exits Quantum, Closely Following Alibaba’s Earlier Move

January 5, 2024

Reuters reported this week that Baidu, China’s giant e-commerce and services provider, is exiting the quantum computing development arena. Reuters reported � Read more…

Choosing the Right GPU for LLM Inference and Training

December 11, 2023

Accelerating the training and inference processes of deep learning models is crucial for unleashing their true potential and NVIDIA GPUs have emerged as a game- Read more…

Shutterstock 1179408610

Google Addresses the Mysteries of Its Hypercomputer 

December 28, 2023

When Google launched its Hypercomputer earlier this month (December 2023), the first reaction was, "Say what?" It turns out that the Hypercomputer is Google's t Read more…

Comparing NVIDIA A100 and NVIDIA L40S: Which GPU is Ideal for AI and Graphics-Intensive Workloads?

October 30, 2023

With long lead times for the NVIDIA H100 and A100 GPUs, many organizations are looking at the new NVIDIA L40S GPU, which it’s a new GPU optimized for AI and g Read more…

AMD MI3000A

How AMD May Get Across the CUDA Moat

October 5, 2023

When discussing GenAI, the term "GPU" almost always enters the conversation and the topic often moves toward performance and access. Interestingly, the word "GPU" is assumed to mean "Nvidia" products. (As an aside, the popular Nvidia hardware used in GenAI are not technically... Read more…

Shutterstock 1606064203

Meta’s Zuckerberg Puts Its AI Future in the Hands of 600,000 GPUs

January 25, 2024

In under two minutes, Meta's CEO, Mark Zuckerberg, laid out the company's AI plans, which included a plan to build an artificial intelligence system with the eq Read more…

Google Introduces ‘Hypercomputer’ to Its AI Infrastructure

December 11, 2023

Google ran out of monikers to describe its new AI system released on December 7. Supercomputer perhaps wasn't an apt description, so it settled on Hypercomputer Read more…

  • arrow
  • Click Here for More Headlines
  • arrow
HPCwire