A MIchigan State University research team is tapping the power of The University of Texas at Austin’s Texas Advanced Computing Center (TACC) supercomputers to help better to understand DNA bending and repair mechanisms.
DNA damage is a natural biological process that happens every time cells divide and multiply. External factors such as overexposure to sunlight can also damage DNA. Consequently, DNA repair is vital for preserving the composition of the genome. Michigan State University professor of biochemistry and molecular biology Michael Feig needed supercomputing to study the molecular-level dynamics involved in this process, and as a user of the NSF Extreme Science and Engineering Discovery Environment (XSEDE), he has tasked the TACC’s Ranger and Stampede supercomputers to accelerate his research.
Dr. Feig’s research focus is on understanding how the human body recognizes damaged DNA and initiates repair. In particular, he studies the proteins MutS and MSH2-MSH6, which recognize defective DNA and initiate DNA repair. Natural DNA repair occurs when proteins like MutS (the primary protein responsible for recognizing a variety of DNA mismatches) scan the DNA, identify a defect, and recruit other enzymes to carry out the actual repair, using computational methods in order to study the structure, dynamics, and energetics of biological macromolecules such as proteins or nucleic acids, particularly concentrating in two areas: 1) The modeling of large supramolecular assemblies in atomic detail and 2) the accurate prediction of native protein structures.
On his MSU faculty Web page, Dr. Feig cites an example of a supramolecular complex his team is investigating, the interaction between the E.coli mismatch recognition protein MutS and DNA with mismatched or missing base pairs. MutS recognizes defective DNA after replication and initiates a multi-step process that leads to DNA repair. Therefore he observes that a detailed understanding of the DNA mismatch repair system is relevant for some types of cancer where the repair process is compromised.
Starting from crystal structures of the MutS protein-DNA complex, the research team applies computer simulation techniques to look at energetic and dynamic aspects of this system.
Dr. Feig notes that prediction of protein structures from sequence has seen great progress through recent methodological advances and the availability of an increasing number of structural templates from experimental protein structures. It is now often possible to generate approximate predictions that capture many of the general features of the native fold, but says that it remains challenging to reach levels of accuracy that are comparable to experimental data unless structures from closely related sequences are available. Consequently, his team is working on new methods that allow refinement of approximate predictions towards more native-like structures by using new enhanced sampling techniques in combination with an accurate energetic description.
“We need high-level atomic resolution simulations to get insights into the answers we are searching for and we cannot run them on ordinary desktops. These are expensive calculations for which we need hundreds of CPUs to work simultaneously and TACC resources made that possible, Dr. Feig notes in a TACC release. “The key here is to understand how these defects are recognized, he continues. “DNA damage occurs frequently and if you couldn’t repair your DNA, then you won’t live for very long.” That would be because damaged DNA, if left unrepaired, can compromise cells and lead to diseases such as cancer.
Check out the video below from the TACC:
Dr. Feig, who has used national supercomputing resources since he was a graduate student in 1998, is applying large-scale computer simulations to gain a detailed understanding of the cellular recognition process. Numerical simulations provide a very detailed view down to the atomistic level of how MutS and MSH2-MSH6 scan DNA and identify which DNA needs to be repaired. Because the systems are complex, the research requires large amounts of computer resources, on the order of tens of millions of CPU core hours over many years.
“We need high-level atomic resolution simulations to get insights into the answers we are searching for and we cannot run them on ordinary desktops,” Dr. Feig observes in the release. “These are expensive calculations for which we need hundreds of CPUs to work simultaneously and the Texas Advanced Computing Center (TACC) resources made that possible.”
As a user of the National Science Foundation’s Extreme Science and Engineering Discovery Environment (XSEDE), Dr. Feig tasked TACC’s Ranger and Stampede supercomputers to accelerate his research. Ranger served the national open science community for five years and was replaced by Stampede (the sixth most powerful supercomputer in the world) in January 2013.
Stampede is a Dell PowerEdge C8220 Cluster with Intel Xeon Phi coprocessors, and as one of the largest computing systems in the world for open science research the system provides unprecedented computational capabilities to the national research community, enabling breakthrough science that has never before been possible. The scale of Stampede delivers opportunities in computational science and technology research, from highly parallel algorithms to high-throughput computing, and from scalable visualization to next generation programming languages.
Any researcher at a U.S. institution can submit a proposal to request an allocation of cycles on the system. The request must describe the research, justify the need for such a powerful system to achieve new scientific discoveries, and demonstrate that the proposer’s team has the expertise to utilize the resource effectively.
TACC’s medical informatics programs coordinator Matt Cowperthwaite notes in the TACC release that Dr. Feig’s research is enormously important for advancing understanding of how cells repair the mistakes that inevitably occur during DNA replication, noting that: “For the first time, we have a mechanistic insight of how MutS finds mutations. This is extremely important research because the process of mutation underlies some of the deadliest diseases to affect humans, such as cancer.”
Dr. Feig agrees, and while he acknowledges that many challenges lie ahead in this field of research, increased understanding of the different and important biological roles and functions of the many proteins in the human body with functions work will be a driving force for research in the near future.