The structural effect of point mutations
How do we tell a genuine mutational effect from the molecule’s own flexibility, and why do some residues respond from far away?
The question sounds elementary and is not. Comparing a wild-type structure with its mutants, the variation attributable to the substitution is buried in the intrinsic flexibility of the molecule and in variation caused by crystallisation conditions.
With Jacques Chomilier and Suvethigaa Shanthirabalan, we showed that the second source in fact dominates the first — but that once displacements are normalised by local flexibility, the very small movements of buried residues and of residues in regular secondary structure turn out to be comparatively large. The method also identifies residues that respond at a distance from the mutated site, which a purely local analysis would miss.
Its limitation is that it needs around twenty structures to estimate normal variability. Estimating that variability from the normal modes of the wild-type structure instead is work in progress.
Papers
Structural effects of point mutations in proteins Proteins: Structure, Function, and Bioinformatics, 2018 DOI
Analyses of displacements resulting from a point mutation in proteins Journal of Structural Biology, 2020 DOI
Contribution to the prediction of the fold code: application to immunoglobulin and flavodoxin cases PLOS ONE, 2015 DOI
Two book chapters develop the same material: Impact of a point mutation in a protein structure (ISTE / Wiley, 2021) and Analyses of mutation displacements from homology models (Methods in Molecular Biology, Springer, 2023). See Publications.