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Research

Biological systems - including the simplest cells - exhibit a broad range of functions to thrive in their environment. Research in the Imperial College Centre for Synthetic Biology is focused on the possibility of engineering the underlying biochemical processes to solve many of the challenges facing society, from healthcare to sustainable energy. In particular, we model, analyse, design and build biological and biochemical systems in living cells and/or in cell extracts, both exploring and enhancing the engineering potential of biology.

As part of our research we develop novel methods to accelerate the celebrated Design-Build-Test-Learn synthetic biology cycle. As such research in the Centre for Synthetic Biology highly multi- and interdisciplinary covering computational modelling and machine learning approaches; automated platform development and genetic circuit engineering ; multi-cellular and multi-organismal interactions, including gene drive and genome engineering; metabolic engineering; in vitro/cell-free synthetic biology; engineered phages and directed evolution; and biomimetics, biomaterials and biological engineering.

Publications

Citation

BibTex format

@article{Harrison:2019:10.1021/acs.jctc.9b00112,
author = {Harrison, RM and Romano, F and Ouldridge, TE and Louis, AA and Doye, JPK},
doi = {10.1021/acs.jctc.9b00112},
journal = {Journal of Chemical Theory and Computation},
pages = {4660--4672},
title = {Identifying physical causes of apparent enhanced cyclization of short DNA molecules with a coarse-grained model},
url = {http://dx.doi.org/10.1021/acs.jctc.9b00112},
volume = {15},
year = {2019}
}

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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - DNA cyclization is a powerful technique to gain insight into the nature of DNA bending. While the worm-like chain model provides a good description of small to moderate bending fluctuations, it is expected to break down for large bending. Recent cyclization experiments on strongly-bent shorter molecules indeed suggest enhanced flexibility over and above that expected from the worm-like chain. Here, we use a coarse-grained model of DNA to investigate the subtle thermodynamics of DNA cyclization for molecules ranging from 30 to 210 base pairs. As the molecules get shorter we find increasing deviations between our computed equilibrium j-factor and the classic worm-like chain predictions of Shimada and Yamakawa for a torsionally aligned looped molecule. These deviations are due to sharp kinking, first at nicks, and only subsequently in the body of the duplex. At the shortest lengths, substantial fraying at the ends of duplex domains is the dominant method of relaxation. We also estimate the dynamic j-factor measured in recent FRET experiments. We find that the dynamic j-factor is systematically larger than its equilibrium counterpart - with the deviation larger for shorter molecules - because not all the stress present in the fully cyclized state is present in the transition state. These observations are important for the interpretation of recent cyclization experiments, suggesting that measured anomalously high j-factors may not necessarily indicate non-WLC behavior in the body of duplexes.
AU  - Harrison,RM
AU  - Romano,F
AU  - Ouldridge,TE
AU  - Louis,AA
AU  - Doye,JPK
DO  - 10.1021/acs.jctc.9b00112
EP  - 4672
PY  - 2019///
SN  - 1549-9618
SP  - 4660
TI  - Identifying physical causes of apparent enhanced cyclization of short DNA molecules with a coarse-grained model
T2  - Journal of Chemical Theory and Computation
UR  - http://dx.doi.org/10.1021/acs.jctc.9b00112
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31282669
UR  - http://hdl.handle.net/10044/1/71458
VL  - 15
ER  -