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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
59
26-POS
Board 26
Molecular Recognition of Intrinsically Disordered Motifs and the Design of High(Er)
Affinity Biomimetic Binders
Elisa Fadda
.
Maynooth University, Maynooth, Ireland.
Conformational disorder is a distinctive and functional feature of many proteins involved in
regulatory and signalling pathways, where intrinsically disordered regions (IDRs) are often
involved in transient and reversible protein-protein interactions (PPI)[1,2]. This class of PPIs
differ significantly from obligate PPIs in that they usually involve small surface areas, and
varying degrees of folding-on-site upon binding. Both of these aspects contribute to modulate
binding affinity[3]. Conformational plasticity is an architectural advantage for proteins involved
in structuring reversible macromolecular assemblies and also to confer broad binding specificity
towards a variety of different receptors[4]. Therefore understanding the structure, energetics, and
dynamics of molecular recognition of specific disordered motifs at the atomistic level of detail
can allows us to consider reversible PPIs as targets for the design of high affinity biomimetic
binders. In this work I will describe how extensive sampling via molecular dynamics (MD)
simulations can reveal important clues that help our understanding of the molecular recognition
of specific disordered motifs, thus can inform the biomimetic design process. More specifically I
will discuss the molecular basis for the binding promiscuity of the extreme C-terminus of the p53
tumour suppressor, and how we are implementing the biomimetic design strategy in the case of
the Xeroderma pigmentosum complementation group A (XPA)[5, 6], a key scaffolding protein
involved in the nucleotide excision repair (NER) pathway.
References:
1. Dyson HJ and Wright PE, Nat Rev Mol Cell Biol (2005), 6:197-208
2. Perkins et al, Structure (2010), 18:1233-43.
3. Michielssen et al, Biophys J (2015), 108:2585-90.
4. Fadda, E., Comp Struct Biotech J (2016), 18:78-85.
5. Fadda, E., Biophys J (2013), 104:2503-11.
6. Fadda, E., PROTEINS (2015) 83:1341-51.