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Conformational Ensembles from Experimental Data
and Computer Simulations
Saturday Speaker Abstracts
15
In Silico Identification of Rescue Sites by Double Force Scanning
Matteo Tiberti
1
, Alessandro Pandini
2
, Franca Fraternali
3,4,5
,
Arianna Fornili
1,5
.
1
Queen Mary University of London, London, United Kingdom,
2
Brunel University London,
London, United Kingdom,
3
King’s College London, London, United Kingdom,
4
The Francis
Crick institute, London, United Kingdom,
5
The Thomas Young Centre for Theory and
Simulation of Materials, London, United Kingdom.
Deleterious amino acid changes in proteins can be compensated by second-site rescue mutations.
These compensatory mechanisms can be mimicked by the binding of small molecules, so that the
position of rescue mutations can be used to identify possible druggable regions on the protein
surface for the reactivation of damaged mutants
1
.
Here we present the Double Force Scanning (DFS) method
2
, the first general computational
approach to detect rescue sites that use compensatory mechanisms mediated by backbone
dynamics. The method is based on an elastic network model and on the application of external
forces to mimic the effect of mutations. All the possible residue pairs in the protein are scanned
and a rescue effect is detected when the simultaneous application of forces at the two sites affects
the protein structure less than a force at a single site. The second-site residues that make the
protein structure most resilient to the effect of single mutations are then identified.
We tested DFS predictions against two datasets containing experimentally validated and putative
evolutionary-related rescue sites, finding a remarkably good agreement between predictions and
reference data. Indeed, half of the experimental rescue sites in the tumour suppressor protein p53
was correctly predicted by DFS, with 65% of remaining sites in contact with DFS predictions.
Similar results were found for other proteins in the evolutionary dataset. Finally, we show how
the prediction of rescue sites can be used to identify potential pockets for the binding of
reactivating drugs.
1. Wassman C.D., et al. (2013) Nat Commun, 4, 1407-1409
2. Tiberti M., Pandini A., Fraternali F., Fornili A., submitted.