Dr Sarah Harris
- Job title: Associate Professor of Biological Physics
- Email: firstname.lastname@example.org
- Telephone: +44(0)113 343 3816
- Faculty: Engineering and Physical Sciences
- School: Physics and Astronomy
- Location: 9.61 EC Stoner
- Areas of expertise: Biomolecular simulation; biological physics; DNA topology
- Website links: ORCHID
To address the biggest mechanistic questions in molecular biophysics, such as how the cellular transport system works, or how the cell co-ordinates mitosis, I believe we need multiple biophysical tools, including theory and computation, and a strong collaborative research community. In my research, I have used molecular dynamics (MD) simulations to explore the response of DNA to stress, and am part of the core development team for the mesoscale modelling tool “Fluctuating Finite Element Analysis” which uses continuum mechanics to describe biomolecular dynamics from volumetric information, such as is provided by cryo-Electron Microscopy.
I am an advocate for using physical methods to describe biology, and for the use of computational tools in science and engineering. I am the incoming Chair of the Computational Collaborative Project in Biomolecular simulation (from November 2020), which is an EPSRC funded UK network supporting biomolecular simulation.
Detailed research programme
DNA supercoiling and topology
Circular DNAs are found throughout biology. Bacterial and mitochondrial genomes are circular. In eukaryotes, extrachromosomal circular DNAs (eccDNA) can be found in the range of only a few hundred base pairs, up to large, gene containing extrachromosomal DNAs (ecDNAs). Oncogenes carried on extrachromosomal DNAs are frequently amplified, and provide a mechanism for tumour heterogeneity, which contributes to drug resistance and poor clinical outcomes from chemotherapy. Circular DNA sequences are also under development as gene therapy vectors. Unlike linear sequences, circular DNAs can store superhelical stress as supercoiling, because the ends of the DNA are restrained. We use atomistic simulations to predict the structure of supercoilied DNA (right-hand image). We have shown that supercoiling compacts the DNA, and can also introduce single stranded regions at high levels of under-twisting stress.
Mesoscale Biosimulation with Fluctuating Finite Element Analysis (FFEA)
FFEA is a new mesoscale computational tool for low resolution modelling of the dynamics of large biomacromolecules and their complexes. FFEA uses continuum mechanics to simulate proteins and other globular macromolecules. It combines conventional Finite Element methods with thermal noise, and is appropriate for simulations at length-scales in the range of 10nm to 500nm, where there are fewer modelling tools. It requires 3D volumetric information as input, which can be low resolution structural information such as cryo-Electron-Tomography maps (e.g left-hand image), or atomistic co-ordinates. We have applied FFEA to model molecular motors such as rotary ATPases (middle image); cytoplasmic dynein, which transports cargo along a microtubule track; and the kinetochore, which mediates cell division.