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!

Google Announces Sixth-generation AI Chip, a TPU Called Trillium

May 17, 2024

On Tuesday May 14th, Google announced its sixth-generation TPU (tensor processing unit) called Trillium.  The chip, essentially a TPU v6, is the company's latest weapon in the AI battle with GPU maker Nvidia and clou Read more…

ISC 2024 Student Cluster Competition

May 16, 2024

The 2024 ISC 2024 competition welcomed 19 virtual (remote) and eight in-person teams. The in-person teams participated in the conference venue and, while the virtual teams competed using the Bridges-2 supercomputers at t Read more…

Grace Hopper Gets Busy with Science 

May 16, 2024

Nvidia’s new Grace Hopper Superchip (GH200) processor has landed in nine new worldwide systems. The GH200 is a recently announced chip from Nvidia that eliminates the PCI bus from the CPU/GPU communications pathway.  Read more…

Europe’s Race towards Quantum-HPC Integration and Quantum Advantage

May 16, 2024

What an interesting panel, Quantum Advantage — Where are We and What is Needed? While the panelists looked slightly weary — their’s was, after all, one of the last panels at ISC 2024 — the discussion was fascinat Read more…

The Future of AI in Science

May 15, 2024

AI is one of the most transformative and valuable scientific tools ever developed. By harnessing vast amounts of data and computational power, AI systems can uncover patterns, generate insights, and make predictions that Read more…

Some Reasons Why Aurora Didn’t Take First Place in the Top500 List

May 15, 2024

The makers of the Aurora supercomputer, which is housed at the Argonne National Laboratory, gave some reasons why the system didn't make the top spot on the Top500 list of the fastest supercomputers in the world. At s Read more…

Google Announces Sixth-generation AI Chip, a TPU Called Trillium

May 17, 2024

On Tuesday May 14th, Google announced its sixth-generation TPU (tensor processing unit) called Trillium.  The chip, essentially a TPU v6, is the company's l Read more…

Europe’s Race towards Quantum-HPC Integration and Quantum Advantage

May 16, 2024

What an interesting panel, Quantum Advantage — Where are We and What is Needed? While the panelists looked slightly weary — their’s was, after all, one of Read more…

The Future of AI in Science

May 15, 2024

AI is one of the most transformative and valuable scientific tools ever developed. By harnessing vast amounts of data and computational power, AI systems can un Read more…

Some Reasons Why Aurora Didn’t Take First Place in the Top500 List

May 15, 2024

The makers of the Aurora supercomputer, which is housed at the Argonne National Laboratory, gave some reasons why the system didn't make the top spot on the Top Read more…

ISC 2024 Keynote: High-precision Computing Will Be a Foundation for AI Models

May 15, 2024

Some scientific computing applications cannot sacrifice accuracy and will always require high-precision computing. Therefore, conventional high-performance c Read more…

Shutterstock 493860193

Linux Foundation Announces the Launch of the High-Performance Software Foundation

May 14, 2024

The Linux Foundation, the nonprofit organization enabling mass innovation through open source, is excited to announce the launch of the High-Performance Softw Read more…

ISC 2024: Hyperion Research Predicts HPC Market Rebound after Flat 2023

May 13, 2024

First, the top line: the overall HPC market was flat in 2023 at roughly $37 billion, bogged down by supply chain issues and slowed acceptance of some larger sys Read more…

Top 500: Aurora Breaks into Exascale, but Can’t Get to the Frontier of HPC

May 13, 2024

The 63rd installment of the TOP500 list is available today in coordination with the kickoff of ISC 2024 in Hamburg, Germany. Once again, the Frontier system at 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…

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…

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…

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 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…

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…

Nvidia’s New Blackwell GPU Can Train AI Models with Trillions of Parameters

March 18, 2024

Nvidia's latest and fastest GPU, codenamed Blackwell, is here and will underpin the company's AI plans this year. The chip offers performance improvements from Read more…

Some Reasons Why Aurora Didn’t Take First Place in the Top500 List

May 15, 2024

The makers of the Aurora supercomputer, which is housed at the Argonne National Laboratory, gave some reasons why the system didn't make the top spot on the Top Read more…

Leading Solution Providers

Contributors

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…

Eyes on the Quantum Prize – D-Wave Says its Time is Now

January 30, 2024

Early quantum computing pioneer D-Wave again asserted – that at least for D-Wave – the commercial quantum era has begun. Speaking at its first in-person Ana Read more…

The GenAI Datacenter Squeeze Is Here

February 1, 2024

The immediate effect of the GenAI GPU Squeeze was to reduce availability, either direct purchase or cloud access, increase cost, and push demand through the roof. A secondary issue has been developing over the last several years. Even though your organization secured several racks... Read more…

Intel Plans Falcon Shores 2 GPU Supercomputing Chip for 2026  

August 8, 2023

Intel is planning to onboard a new version of the Falcon Shores chip in 2026, which is code-named Falcon Shores 2. The new product was announced by CEO Pat Gel Read more…

The NASA Black Hole Plunge

May 7, 2024

We have all thought about it. No one has done it, but now, thanks to HPC, we see what it looks like. Hold on to your feet because NASA has released videos of wh Read more…

GenAI Having Major Impact on Data Culture, Survey Says

February 21, 2024

While 2023 was the year of GenAI, the adoption rates for GenAI did not match expectations. Most organizations are continuing to invest in GenAI but are yet to Read more…

How the Chip Industry is Helping a Battery Company

May 8, 2024

Chip companies, once seen as engineering pure plays, are now at the center of geopolitical intrigue. Chip manufacturing firms, especially TSMC and Intel, have b Read more…

Q&A with Nvidia’s Chief of DGX Systems on the DGX-GB200 Rack-scale System

March 27, 2024

Pictures of Nvidia's new flagship mega-server, the DGX GB200, on the GTC show floor got favorable reactions on social media for the sheer amount of computing po Read more…

  • arrow
  • Click Here for More Headlines
  • arrow
HPCwire