WALTZ-DB 2.0: an updated database containing structural information of experimentally determined amyloid-forming peptides

Abstract

Transition of soluble proteins into insoluble amyloid fibrils is driven by self-propagating short sequence stretches. However, accurate prediction of aggregation determinants remains challenging. Here, we describe WALTZ-DB 2.0, an updated and significantly expanded open-access database providing information on experimentally determined amyloid-forming hexapeptide sequences (http://waltzdb.switchlab.org/). We have updated WALTZ-DB 2.0 with new entries, including: (i) experimental validation of an in-house developed dataset of 229 hexapeptides, using electron microscopy and Thioflavin-T binding assays; (ii) manual curation of 98 amyloid-forming peptides isolated from literature. Furthermore, the content has been expanded by adding novel structural information for peptide entries, including sequences of the previous version. Using a computational methodology developed in the Switch lab, we have generated 3D-models of the putative amyloid fibril cores of WALTZ-DB 2.0 entries. Structural models, coupled with information on the energetic contributions and fibril core stabilities, can be accessed through individual peptide entries. Customized filtering options for subset selections and new modelling graphical features were added to upgrade online accessibility, providing a user-friendly interface for browsing, downloading and updating. WALTZ-DB 2.0 remains the largest open-access repository for amyloid fibril formation determinants and will continue to enhance the development of new approaches focused on accurate prediction of aggregation prone sequences.

A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

“…Finally, the thermodynamically stable segments identified here largely overlap with aggregation-prone segments (APRs) previously found to be necessary for amyloid nucleation and elongation 10,11,14 . This does not exclude modulating effects of other regions, even by regions that are not incorporated in the fibre core, such as the fuzzy coat observed in many amyloids 29 .…”

“…Instead, main-chain H-bond saturation is here provided by quaternary H-bonds that staple adjacent chains into the archetypal amyloid cross-b sheet running perpendicular to the fibril axis. Second, while short amyloid peptides can organise into both parallel and antiparallel b-sheets 10,11 , longer or full-length protein fibrils are so far primarily found forming parallel b-sheet structures. As a result, side chain interactions along the fibre axis result mainly from the registered stacking of identical side chains, a situation that is unique to amyloid assembly.…”

Structure-based machine-guided mapping of amyloid sequence space reveals uncharted sequence clusters with higher solubilities

“…For peptide aggregation propensity, we used a dataset of 1402 non-redundant hexapeptides contained in the WALTZ-DB 2.0 repository 32 . This database is the largest currently available resource of experimentally characterised amyloidogenic peptides.…”

“…As an initial test of the prediction accuracy of the regression model, we performed leave-one-out cross-validation on the training dataset 32 and performance metrics were determined on a peptide basis. Due to the extensive size of the dataset, comparison to other software was performed only with methods supporting multiple sequence input and a non-binary scoring function, since performances were compared using receiver operating characteristic (ROC) analysis 33 .…”

Rational optimization of a monoclonal antibody improves the aggregation propensity and enhances the CMC properties along the entire pharmaceutical process chain

“…6,19 Notably, a variety of in silico tools identifying aggregation-prone regions (APRs) were developed, emphasizing the strong demand for the prediction and prevention of protein particle formation. [20][21][22][23][24][25][26][27][28][29][30][31] Particular attention was paid to the Solubis method, 32 which was used in a previous study 6 to predict sequence variants of a therapeutic mAb (called mAb2) with reduced intrinsic aggregation propensity (TANGO) 33 under consideration of the thermodynamic stability of the native structure (FoldX). 34 A single amino acid exchange (S52R) in complementarity determining region 2 (CDR2) of the light chain (LC) was shown to diminish an APR that triggered aggregation of transiently expressed mAb2.…”