Finishing up a lingering project from your PhD almost a year into your postdoc is a great feeling, especially when it has actually been about 3 years in the making.
Though somewhat outside of the usual scope of activities in OPIG, I encourage you to take a look if the below summary grabs your interest. The full paper and supporting materials (including some movies which took entirely too long to make) can be found at https://pubs.acs.org/doi/abs/10.1021/jacs.9b12264.
Category Archives: Protein Folding
The evolution of contact prediction – a new paper
I’m so pleased to be able to write about our work on The evolution of contact prediction: evidence that contact selection in statistical contact prediction is changing (Bioinformatics btz816). Contact prediction – the prediction of parts of the amino-acid chain that are close together – has been critical to improving the ability of scientists to predict protein structures over the last decade. Here we look at the properties of these predictions, and what that might mean for their use.
The paper begins with a question. If contact prediction methods are based on statistical properties of sequence alignments, and those alignments are generated in the presence of ecological and physical constraints, what effect do the physical constraints have on the statistical properties of real sequence alignments? More concisely: when we predict contacts, do we predict particularly important contacts?
Continue readingWhat is the hydrophobic-polar (HP) model?
Proteins are fascinating. They are ubiquitous in living organisms, carrying out all kinds of functions: from structural support to unbelievably powerful catalysis. And yet, despite their ubiquity, we are still bemused by their functioning, not to mention by how they came to be. As computational scientists, our research at OPIG is mostly about modelling proteins in different forms. We are a very heterogeneous group that leverages approaches of diverse scale: from modelling proteins as nodes in a complex interaction network, to full atomistic models that help us understand how they behave.
Continue readingStart2Fold: A database of protein folding and stability data
Hydrogen/deuterium exchange (HDX) experiments are used to probe the tertiary structures and folding pathways of proteins. The rate of proton exchange between a given residue’s backbone amide proton and the surrounding solvent depends on the solvent exposure of the residue. By refolding a protein under exchange conditions, these experiments can identify which regions quickly become solvent-inaccessible, and which regions undergo exchange for longer, providing information about the refolding pathway.
Although there are many examples of individual HDX experiments in the literature, the heterogeneous nature of the data has deterred comprehensive analyses. Start2Fold (Start2Fold.eu) [1] is a curated database that aims to present protein folding and stability data derived from solvent-exchange experiments in a comparable and accessible form. For each protein entry, residues are classified as early/intermediate/late based on folding data, or strong/medium/weak based on stability data. Each entry includes the PDB code, length, and sequence of the protein, as well as details of the experimental method. The database currently includes 57 entries, most of which have both folding and stability data. Hopefully, this database will grow as scientists add their own experimental data, and reveal useful information about how proteins refold.
The folding data available in Start2Fold is visualised in the figure below, with early, intermediate and late folding residues coloured light, medium and dark blue, respectively.
[1] Pancsa, R., Varadi, M., Tompa, P., Vranken, W.F., 2016. Start2Fold: a database of hydrogen/deuterium exchange data on protein folding and stability. Nucleic Acids Res. 44, D429-34.