Exploring the sequence features determining amyloidosis in human antibody light chains

Abstract

The light chain (AL) amyloidosis is caused by the aggregation of light chain of antibodies into amyloid fibrils. There are plenty of computational resources available for the prediction of short aggregation-prone regions within proteins. However, it is still a challenging task to predict the amyloidogenic nature of the whole protein using sequence/structure information. In the case of antibody light chains, common architecture and known binding sites can provide vital information for the prediction of amyloidogenicity at physiological conditions. Here, in this work, we have compared classical sequence-based, aggregation-related features (such as hydrophobicity, presence of gatekeeper residues, disorderness, β-propensity, etc.) calculated for the CDR, FR or VL regions of amyloidogenic and non-amyloidogenic antibody light chains and implemented the insights gained in a machine learning-based webserver called “VLAmY-Pred” (https://web.iitm.ac.in/bioinfo2/vlamy-pred/). The model shows prediction accuracy of 79.7% (sensitivity: 78.7% and specificity: 79.9%) with a ROC value of 0.88 on a dataset of 1828 variable region sequences of the antibody light chains. This model will be helpful towards improved prognosis for patients that may likely suffer from diseases caused by light chain amyloidosis, understanding origins of aggregation in antibody-based biotherapeutics, large-scale in-silico analysis of antibody sequences generated by next generation sequencing, and finally towards rational engineering of aggregation resistant antibodies.