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Description of information transfer across macromolecules by concerted conformational changes

Periodic Reporting for period 3 - CONCERT (Description of information transfer across macromolecules by concerted conformational changes)

Reporting period: 2018-07-01 to 2019-12-31

The main goal of the project is to develop a method to characterise large scale motions in macromolecules. Motions of this type are key for the transfer of information in biology but are very challenging to characterise both experimentally and computationally. The experimental challenge is associated with the paucity of experimental observables that are sensitive to the degree of correlation of large scale motions. The computational challenge is associated with simulating large multi-domain proteins with motions in relatively slow timescales that cannot be studied with even the fastest computers available.

Characterising this type of motions is important because interfering with information transfer processes in biology offers opportunities for developing drugs. This is especially the case when tumour cells or those of pathogens acquire mutations or other modifications that render them insensitive to the treatments currently in the clinic. Understanding how the targets of these drugs play a role in information transfer processes can reveal novel ways of targeting them that can be exploited by scientists experts in discovering drugs. An example of the problem of resistance is a late stage of prostate cancer known as castration resistant prostate cancer in which patients cease to respond to hormone therapy, the first line treatment for this very common disease.

The objectives of this project are to develop a method for characterising large scale concerted motions and apply it to understanding the role that they play in the activation of the androgen receptor. This protein plays a key role in the activation of the genes that are responsible for the development of the male phenotype, is activated by the hormone testosterone and is also the most important therapeutic target in all stages of prostate cancer.
Since the project started the team has worked at producing samples of the androgen receptor for characterising their structures and motions. Samples of protein containing the N-terminal, DNA binding and hormone binding domains have been produced in sufficient amounts for biophysical studies that have revealed, for example, that the N-terminal domain interacts with a member of the basal transcription machinery by adopting a specific structure conformation. Experiments have also been conducted to show that the N-terminal domain has a very high propensity to aggregate into distinct species that we think may play a role in information transfer and, therefore, in the activation process.
The project is going according to the plan. We trust that the project will lead, in the long term, to the development of new therapies for castration resistant prostate cancer.