Understanding proteins with dynamic behavior from a biophysical angle; application to categorise and design novel (chimeric) GPCRs

The field of protein design is currently able to design proteins that
fold into a well-delineated 3D structure using the traditional protein
structure-function paradigm. However, many proteins display
dynamic behaviour, where multiple conformations have to be taken
into account, and their design remains challenging. In this project, the
aim is to extend the structure-function paradigm in protein design by
including the overall expected biophysical behaviour of the protein.
This is done by including features in the description of proteins that
are not evident from protein sequence nor structure, but that
evolution conserves in order to preserve function (e.g., dynamics). By
defining and employing biophysical constraints, in addition to
available sequence, structure and evolutionary information, I intend
to improve the design of protein chimeras, which can provide insights
in a protein’s functional mechanisms and 3D structures. In this
project, I will focus on G-protein coupled receptors (GPCRs). GPCRs
have been shown to be strongly implicated in numerous diseases.
However, the majority of GPCRs have not been successfully
drugged: much of the difficulty in doing so can be attributed their
innate conformational flexibility and sequence variability. GPCRs thus
make an excellent target for this project as they are proteins with
ambiguous and dynamic behaviour, and with an enormous
therapeutic and therefore economical potential