NERSCPowering Scientific Discovery Since 1974



March 1, 2008


The image shows the relationship between Topoisomerase and DNA. Topoisomerase (in green) is an enzyme that unknots the DNA, allowing proteins to transcribe and form a new set of genetic materials during cell division.

A team from the University of California at Irvine is exploring the complex interactions of human DNA with proteins and nanoparticles in a research that tackles  key problems in designing and delivering  anti-cancer drugs and gene therapy. 

The research team, headed by Ioan  Andricioaei, is using the computer power  and services at NERSC to better understand how certain proteins affect DNA’s  behavior during cell replication. The  research also looks at the dynamics  between DNA and polyamidoamine  (PAMAM) dendrimers, nano-particles that  could be used to transport drugs and  genetic materials into the body for treatment. 

The research builds on previous  molecular dynamic simulations by the  team. The 2008 allocation of 7.4 million  MPP hours represents the first major  undertaking at NERSC by the Irvine  research team. 

“Our simulations require thousands of  processors to simulate the vast conformational changes we are attempting to study,”  says Jeff Wereszczynski of the  Andricioaei team. “With the power of  Franklin (Cray XT4), what used to take us several months we can now do in  weeks.” 

In the first project, the scientists want  to know how an enzyme called topoisomerase I, which loosens the tightly  packed DNA during replication, would  react to topotecan. Topotecan is a chemical compound known to disrupt the  enzyme’s work, and is currently used for  treating ovarian and lung cancer. But  exactly how topoisomerase I and DNA  interact with topotecan isn’t clear.  Understanding their dynamics could lead  to better-designed cancer treatments.  

The research conducted by  Wereszczynski looks specifically at the  energy use and movement of DNA as  supercoils are relaxed, a vital step to  allow cell division, and at how topotecan  affects this function. Previous simulation  work by the team already showed a difference in the mechanisms at which  twisted DNA strands relax without interference from topotecan, so that proteins  can access genetic information and  jumpstart the replication process (Sari  and Andricioaei, Nucleic Acids Research,  2005). 

In the second project, Andricioaei and  Mills aim to figure out how DNA behaves  when it’s attached to a nano-particle such  as PAMAM dendrimer. Does the pairing  alter the structure or properties of both  objects, for example? Does it matter what part of the PAMAM dendrimer surface is used?  

PAMAM dendrimers are tiny, and a  variety of molecules can be easily  attached to their surface. For this reason,  PAMAM dendrimers are considered  promising vehicles for delivering healthy  DNA to fix faulty genes.  

Based on their previous work, the scientists knew that both the DNA and the  dendrimer would become deformed if the  widest edge of a PAMAM dendrimer is  parallel to the axis of a DNA. The DNA  would wrap around the dendrimer while  the dendrimer would flatten against the  DNA. Understanding the energetics and  dynamics behind this interaction is key in  advancing the nanotechnology uinderlying gene therapies further. 

In the third project, the researchers  seek to understand the role of portal pro- tein in the life of a bacteriophage, which infects a bacterium by pushing its genetic  material into the host’s cells. Since the  early 1900s, scientists have discovered  that some viruses can act as parasites  and kill their bacterial hosts. Since antibi- otics are easy to manufacture and store,  the idea of using bacteriophages to treat  illnesses didn’t catch on, except in the  former Soviet Union and Eastern Europe.  

Understanding how bacteriophages  work can lead to better medicines,  including countering the effects of  bioweapons.  

What happens after a bacteriophage  injects its DNA into a bacterial cell is the  focus of the simulation performed by  Jeremiah Nummela in the Andricioaei  group. A bacteriophage consists of a protein shell enclosing its genetic material.  When the viral DNA hijacks the protein synthesis mechanisms of the bacterium  and begins to replicate itself, the process  also involves the forming of capsids.  Capsids are protein shells that would  house these new DNA strands and  become new bacteriophages.  

The DNA strands enter the new capsids through the portal proteins. Importing  the genetic materials through the portal  proteins and packing them tightly  requires a lot of force. Through simulations, the researchers intend to calculate  the interaction between the DNA and portal protein. Andricioaei and Nummela will  use a new method they have developed  to carry out the calculations (Nummela  and Andricioaei, Biophysical Journal,  2007).  Learn more about the research at  Andricioaei’s web site.

About NERSC and Berkeley Lab
The National Energy Research Scientific Computing Center (NERSC) is a U.S. Department of Energy Office of Science User Facility that serves as the primary high-performance computing center for scientific research sponsored by the Office of Science. Located at Lawrence Berkeley National Laboratory, the NERSC Center serves more than 7,000 scientists at national laboratories and universities researching a wide range of problems in combustion, climate modeling, fusion energy, materials science, physics, chemistry, computational biology, and other disciplines. Berkeley Lab is a DOE national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California for the U.S. Department of Energy. »Learn more about computing sciences at Berkeley Lab.