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Periodic Report Summary 1 - AMEMM (Assembly, Mechanism, and Evolution of Macromolecular Machinery)

This document outlines progress made under my four-year FP7 CIG 'AMEMM' (Grant Agreement Number 630988). The proposal as originally submitted described my aims to understand the assembly, mechanism, and evolution of molecular machines. To accomplish this, I proposed a hybrid approach, incorporating 3D in situ electron cryo-tomographic imaging to visualize the structure of the machinery, biophysics to assess the mechanical output of the machinery, and molecular phylogenetics to contextualize these observations against a robust phylogeny. Three broad aims were proposed: first, I described aims to develop methods to structural characterize molecular machinery, using the bacterial flagellar motor and type III secretion systems as the model system. Secondly, I described aims to relate the structures of these macromolecular machines to their mechanical output. Thirdly, I outlined strategies to relate these results to phylogenetics of the component proteins towards understanding the mechanistic aspects of their evolution.

Scientific progress has been excellent, and I have accomplished the majority of my aims for the first two years, and am already ahead of schedule on a number of sub-projects for the coming two years. I have published work on the structure of diverse flagellar motors and directly related these structures to their mechanical output. I have recruited a postdoc to study the analogous archaellar motor with the intent of identifying evolutionary fundamentals to both archaellar and bacterial flagellar evolution. I have worked towards developing a pseudo-atomic model of the flagellar type III secretion system, and have recruited a postdoc to establish robust phylogenies over the component proteins from diverse flagellar motors. We anticipate that these phylogenies will enable us to contextualize and interpret the evolutionary events behind diversification of flagellar motors; these insights, we believe, will be generally applicable to molecular evolution in general.

In addition to scientific progress I have made a major technical advance by constructing a roboticized system that enables routine overnight high-throughput electron cryo-tomographic data collection on a mid-range electron microscope. This development has been greeted with excitement by many members of the community, and enabled collection of large volumes of data towards a major paper published earlier this year in PNAS.

As a result, my research career development is progressing extremely well. Since award of the CIG I have been awarded five additional pieces of grant funding in total providing over £1 000 000 of funds to my lab. I have published a number of papers including the major publication in PNAS, which has received considerable press coverage from the mainstream media, and I have delivered, or am invited to deliver, ten talks on this work at major conferences. I have recruited two postdocs and three PhD students, and hope to recruit a third postdoc in the coming months. These successes have lead me to pass the probationary period at Imperial College where I now hold a permanent position as a Lecturer; I anticipate promotion to Senior Lecturer next academic year.

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United Kingdom


Life Sciences
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