The possibility to study biological processes at the single-molecule level has provided us a tremendously improved understanding of the underlying molecular mechanisms. Through the removal of ensemble averaging, distributions and fluctuations of molecular properties can be characterized, transient intermediates identified, and catalytic mechanisms elucidated. Our group utilizes and further develops novel single-molecule techniques to study problems in the following fields:
DNA-protein interactions
By combining mechanical manipulation of individual DNA molecules with optical microscopy we are able to study the activity of nucleic acid enzymes on the single-molecule level. In collaboration with Charles Richardson (Department of Biological Chemistry and Molecular Pharmacology, HMS) we focus on the study of the DNA replication machinery of the bacteriophage T7. The direct observation of the interactions of the different components of an individual replication complex with the DNA and each other provides valuable insight in the molecular mechanisms controlling DNA replication.
In collaboration with Johannes Walter (Department of Biological Chemistry and Molecular Pharmacology, HMS) we are extending these techniques to study the enzymatic dynamics of the eukaryotic replication fork, using cell-free systems derived from Xenopus eggs.
Furthermore, we are developing novel fluorescence imaging techniques to visualize the interaction of individual, fluorescently labeled proteins with DNA. Using this technique we hope to gain a further understanding of the molecular mechanisms involved in DNA replication, searching mechanisms of DNA-binding factors, and DNA recombination pathways.
The molecular mechanism of viral fusion
In collaboration with the group of Stephen Harrison (Department of Biological Chemistry and Molecular Pharmacology, HMS) we are embarking on an effort to characterize the molecular mechanisms underlying viral membrane fusion. We are reconstituting viral fusion in vitro with only the bare minimum of molecular components and monitoring the dynamics of the fusion process at the single-particle level. These ‘molecular movies’ will allow us to dissect the reaction kinetics at a level of detail inaccessible to conventional ensemble experiments.
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