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Single-molecule biophysics experiments in silico: Toward a physical model of a replisome

Author(s): Edward James

Biomolecular dynamics computational modelling is commonly used to aid in the interpretation of single-molecule investigations. In the near future, it might be possible to completely replace some tests with computational mimics due to the expansion of computing power and the ongoing validation of computational models. Here, utilising a DNA-binding protein as a model case, we provide a guide for conducting single-molecule research in silico. We show how the construction of a coarse-grained model for use in simulations that resemble single-molecule investigations can be guided by atomistic simulations, which are normally restricted to sub-millisecond durations and zeptoliter volumes. We use the model to simulate in silico protein and DNA replacement experiments and force-extension characterisation of protein binding to single-stranded DNA, giving us a clear picture of the underlying mechanics. Finally, we simulate the trombone loop of a replication fork, a substantial complex of proteins and DNA, using the model. The physical and biochemical characteristics of individual biomolecules and biomolecular assemblies can be characterised by single-molecule studies to reveal important details about the mechanisms underlying biological function However, only a small number of degrees of freedom can be simultaneously probed by the majority of experimental methods that work on individual biomolecules, such as force spectroscopy and fluorescent microscopy

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