Abstract
SummaryProteins with highly similar tandem domains have shown an increased propensity for misfolding and aggregation. Several molecular explanations have been put forward, such as swapping of adjacent domains, but there is a lack of computational tools to systematically analyze them. We present the TAndem DOmain Swap Stability predictor (TADOSS), a method to computationally estimate the stability of tandem domain-swapped conformations from the structures of single domains, based on previous coarse-grained simulation studies. The tool is able to discriminate domains susceptible to domain swapping and to identify structural regions with high propensity to form hinge loops. TADOSS is a scalable method and suitable for large scale analyses.Availability and implementationSource code and documentation are freely available under an MIT license on GitHub at https://github.com/lafita/tadoss.Supplementary information Supplementary data are available at Bioinformatics online.
Highlights
Protein misfolding and aggregation is a major problem for cells and organisms, and the cause of severe human diseases like Alzheimer’s
The alchemical free energy difference from TAndem DOmain Swap Stability predictor (TADOSS) correlates well with the free energies obtained in the simulations by Tian and Best (2016), the scale differs by a factor of two approximately (Supplementary Fig. S1)
We find an agreement in the effect of the linker length between the simulated and alchemical free energy differences (Supplementary Fig. S2)
Summary
Protein misfolding and aggregation is a major problem for cells and organisms, and the cause of severe human diseases like Alzheimer’s. Recent studies have shown an increased propensity of aggregation in proteins containing identical domains in tandem (Borgia et al, 2015; Wright et al, 2005). A recent study by Tian and Best (2016) demonstrated using coarse-grained simulations of tandem pairs of identical domains that the difference in stability between the native and the domain-swapped conformations correlates with the swapping propensity. They described an alchemical approach (i.e. simplified model) to estimate the free energy difference of the two conformations that can be generally used to predict domain swapping. Stability predictor (TADOSS), which can be used to systematically find domains susceptible to domain swapping and identify the regions of the structure with the highest propensity to form hinge loops
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