Ioan Andricioaei

Case Study Worksheet

Project Information - Energetics of the Mechano-Chemical Coupling in DNA-Protein and DNA-Nanoparticle Complexes

Project Summary (Scientific Objectives)

Please give a brief description of your project and its scientific objectives for the next 3-5 years.

The interactions of DNA with proteins and nanoparticles are at the heart of several biomedical problems 
such as the design of novel chemotherapeutic drugs, delivery systems for gene therapy, and the 
understanding of DNA packing in viruses. Molecular dynamics (MD) simulations have proven to 
be a valuable tool for gaining an all-atom description of biological systems, and with the aid of 
techniques such as umbrella sampling or trajectory reweighting information may be gained about 
underlying mechanisms, transition states, and reaction rates. We aim to use MD to advance our 
knowledge of these interactions with three distinct projects: 
 

I.) Supercoil Relaxation by Topoisomerases. 
Human topoisomerase I is a crucial enzyme that removes the stress created by DNA supercoils. The 
importance of these enzymes to cellular division makes them a target for anti-cancer drugs, and 
indeed compounds such as topotecan are potent chemotherapeutic drugs which inhibit both religation 
and rotation of the DNA about its axis. Exciting single molecule experiment results that match our 
simulation work show important differences in the rates and mechanisms of relaxation of positive and 
negative supercoils. We are creating free energy profiles for topo/DNA complexes with and without 
topotecan to answer the following questions: (1) What are the mechanisms that allow relaxation of 
supercoils? (2) How are they affected by topotecan? (3) Why is there a difference in positive and 
negative supercoil relaxation, with and without drug? 
 

In addition to topo I, new for this year we will also look at topoisomerase type II system for which 
structures have recently become avaiable. 
 
 

II.) The interaction of DNA with dendrimers. 
Functionalized nanoparticles hold great promise for a number of biomedical applications such as 
delivery systems for gene therapy or targeted drugs. If nanoparticles are to be used for such functions 
their interactions with the delivery molecule must be well understood. Polyamidoamine (PAMAM) 
dendrimers are a promising potential delivery particle because their size and surface chemistry can be 
easily controlled. This project will use MD to look at the interactions between PAMAM dendrimers and 
DNA. The objectives of this study are: (1) understand the nature of the interaction between DNA and 
PAMAM dendrimers, for dendrimers with amine termintations and mixed amine-acetamide 
terminations; (2) calculate the free energy of the interaction; (3) determine how the interaction affects 
the structure of both particles; (4) determine how the orientation of the dendrimer with respect to the 
DNA affects the interaction. 
 

III.) DNA Import and Ejection through Viral Portal Proteins. 
Molecular assemblies that import DNA into the capsids of dsDNA bacteriophage viruses are among the 
strongest known molecular motors, exerting forces exceeding 50 pN, and playing a necessary role in 
the bacteriophage infection cycle. On the basis of electron microscopy and crystal structures of the 
portal protein, early proposed mechanisms involved ATPase driven rotation of the portal protein with 
respect to the capsid. Recent experimental evidence suggests that full rotation does not occur during 
import. 
 

We plan to probe the role of the portal protein using molecular dynamics simulations. Simulations will 
be carried out in which the DNA is pushed through the protein pore by an applied external force with 
the following objectives: (1) A free energy profile for DNA-portal protein interactions will be calculated 
using non-equilibrium free energy relationships; (2) Proposed mechanisms will be evaluated on the 
basis of the qualitative response of the protein to the DNA motion; (3) The system will be described 
using a new method recently developed in our lab for calculating dynamic properties of biomolecular 
systems at low force, from the results of simulations conducted at high force.

Current HPC Usage and Methods

Please list any required or important software, services, or infrastructure (beyond supercomputing and standard storage infrastructure) provided by HPC centers or system vendors.

Gnuplot, 
Mathematica, 
PERL, 
VMD

Please list your current primary codes and their main mathematical methods and/or algorithms. Include quantities that characterize the size or scale of your simulations or numerical experiments; e.g., size of grid, number of particles, basis sets, etc. Also indicate how parallelism is expressed (e.g., MPI, OpenMP, MPI/OpenMP hybrid)

NAMD is a highly efficient Molecular Dynamics package from the Bionumerics Research Group at the University of Illinois at Urbana-Champaign designed specifically for large systems. It is based on the Charm++ parallel programming model and scales to hundreds of processors with the use of an incremental load balancer. The velocity verlet algorithm is used for time stepping and the Particle Mesh Ewald algorithm (PME) is used for calculations of electrostatics (the most costly computations required for MD).

Please list the known limitations/obstacles/bottleneck of resources currently available HPC systems, and in particular, those at NERSC.

HPC Usage and Methods for the Next 3-5 Years

Anticipated changes to codes, mathematical methods and/or algorithms needed to achieve this project's scientific objectives.

Known or Anticipated architectural requirements (e.g., 2 GB memory/core).

Please list any additional required or important software, services, or infrastructure beyond those listed in the previous section.

It is believed that the dominant HPC architecture in the next 3-5 years will incorporate processing elements composed of 10s-1,000s of individual cores. It is unlikely that a programming model based solely on MPI will be effective, or even supported, on these machines. Do you have a strategy for computing in such an environment? If so, please briefly describe it.

What Do You Need from NERSC?

Please tell us what you need from NERSC to meet your project's computing needs over the next 3-5 years. Also please feel free to make any general comments.

General Comments: 
 
Consider the possibility to use GPU for molecular dynamics (see http://www.acellera.com/index.php?arg=acemd), and possibly study feasibility of employing grape-MD 
 
Consider implementing the software optimization (rewrite) for molecular dynamics provided by the Desmond, a scalable parallel package (http://www.tacc.utexas.edu/ta/ta_display.php?ta_id=100732) just recently integrated at TeraGrid that promises significant speed-up of MD algorithms.