Andrew J. Spakowitz - Assistant Professor

Office: Keck Science Building, Room 279
Phone: (650) 736-8733  
E-Mail: ajspakow@stanford.edu
Admin. Associate: Victoria Lee, (650)723-7503
Group Website: http://www.stanford.edu/~ajspakow/

Highest Degree

• Ph.D., California Institute of Technology, 2004

Research Area

Theory of Biological Systems and Complex Fluids

Overview

Our research group utilizes analytical theory and computational techniques to address the physics of biological systems and complex fluids. Our approach makes use of a range of theoretical and computational methods in statistical mechanics and polymer physics, including analytical theory of semiflexible polymers, polymer field theory, Brownian dynamics simulation, and Monte Carlo simulation. We focus on several experimental systems that are of scientific and technological importance, addressing the physical phenomena that underlie the observed behavior. For example, we study the physical manipulation of DNA in single-molecule experiments and in the packaging of an organism’s genome. This theoretical effort aims to understand the exquisite control that Nature has over the DNA molecule and how we can mimic such methods in technological applications.

Single-molecule Biophysics

Single-molecule manipulation plays an important role in our understanding of a wide range of biological processes. Experimental techniques for physically manipulating individual molecules have progressed in resolution to the point where processes that occur on the length scale of a couple of Angstroms can be detected, thus making it possible to directly observe a number of biological phenomena in situ. At this minute length scale, thermal fluctuations play a pivotal role in the physical behavior of these systems and act to compromise the resolution of the experimental measurement. Our theoretical work aims to predict the behavior in single-molecule experiments, providing a robust method to interpret their results and to increase the signal-to-noise ratio. We develop a theoretical framework for predicting the behavior of tethered-bead single-molecule experiments. Using our exact results for the statistical behavior of the molecular tether as a semiflexible polymer, we provide a formalism that is both accurate and easily implemented into experiments. This framework provides the flexibility to address a wide range of outstanding physical issues that play an important role in single-molecule biophysics.

DNA Packaging in Chromatin

Our genome contains roughly a billion base pairs and is approximately 1 meter in length. This DNA strand must be packaged within a nucleus that is about 1 micron across while remaining accessible to the nuclear environment for protein expression. This engineering feat is accomplished by histone proteins that wrap the DNA into a hierarchical structure called chromatin. The first level in this hierarchical assembly is the nucleosome core particle, which consists of 146 base pairs of DNA wrapped around a histone protein complex. We build a model of the nucleosome core particle for comparison with single-molecule experiments in order to assign quantitative values to the adhesion strengths that lead to nucleosome formation. In so doing, we predict the forces that must be overcome to gain access to the packaged genomic code, lending insight into how to condense DNA and maintain accessibility in gene therapy applications. Our long term goal is to systematically address the assembly of chromatin starting from the nucleosomal level and leading to the hierarchical structure of the chromatin fiber.

Viral Packaging of DNA

The capacity of a virus to package, transport, and deliver its genome is realized through the precise manipulation of the DNA (or RNA) strand during various stages of the life cycle of the virus. Each virus has developed specific methods of controlling its genome in order to efficiently invade its specific host cell. Understanding the physical processes that underlie DNA manipulation by viruses is important in the development of viral-based gene therapy applications. Furthermore, the varied methods used by viruses to manipulate DNA demonstrate a variety of different physical techniques that could be exploited in DNA-based technologies. We study the packaging of DNA in viruses using Brownian dynamics and Monte Carlo simulations. We address the internal structure of the DNA strand in order to predict the forces required to package the viral genome and to understand the degree of order necessary for the subsequent ejection of the packaged DNA. Future work will focus on the packaging of single-stranded DNA into Adeno-associated virus in order to optimize packaging for a viral-based gene therapy application.

Publications

1. A. J. Spakowitz. Wormlike chain statistics with twist and fixed ends. Europhys. Lett., 73, 684 (2006). A. J. Spakowitz and Z.-G. Wang. End-to-end distance vector distribution with fixed end orientations for the wormlike chain model. Phys. Rev. E, 72, 041802 (2005).
2. A. J. Spakowitz and Z.-G. Wang. DNA Packaging in Bacteriophage: Is Twist Important? Biophys. J., 88, 3912 (2005). A. J. Spakowitz and Z.-G. Wang. Exact results for a semiflexible polymer chain in an aligning field. Macromolecules, 37, 15, 5814 (2004).
3. A. J. Spakowitz and Z.-G. Wang. Semiflexible polymer solutions. I. phase behavior and single-chain statistics. J. Chem. Phys., 119, 24, 13113 (2003).
4. A. J. Spakowitz and Z.-G. Wang. Semiflexible polymer confined to a spherical surface. Phys. Rev. Lett., 91, 16, 166102 (2003).
5. A. J. Spakowitz and Z.-G. Wang. Free expansion of elastic filaments. Phys. Rev. E, 6406, 6, 061802 (2001).