Protein aggregation: in silico algorithms and applications

Abstract

Protein aggregation is a topic of immense interest to the scientific community due to its role in several neurodegenerative diseases/disorders and industrial importance. Several in silico techniques, tools, and algorithms have been developed to predict aggregation in proteins and understand the aggregation mechanisms. This review attempts to provide an essence of the vast developments in in silico approaches, resources available, and future perspectives. It reviews aggregation-related databases, mechanistic models (aggregation-prone region and aggregation propensity prediction), kinetic models (aggregation rate prediction), and molecular dynamics studies related to aggregation. With a multitude of prediction models related to aggregation already available to the scientific community, the field of protein aggregation is rapidly maturing to tackle new applications.

Keywords: Aggregation kinetics; Aggregation propensity; Algorithm; Molecular dynamics; Peptide assembly; Prediction; Protein aggregation.

Fig. 1

Structural model of an amyloid fibril: a) amyloid fibril of an 11-residue fragment (125–135) of transthyretin protein (PDB: 3ZPK, UniProt ID: P02767), b) a protofibril , c) intersheet steric zipper formation, and d) the intersheet hydrogen bonds along the fibril axis

Fig. 2

Structure and predicted APRs in lambda light chain (A55): a structure of AL55 modelled using ABodyBuilder (Leem et al. 2016), b cryo-EM structure of AL55 amyloid protofibril (PDB: 6HUD), and c residue contacts in the fibril. The atoms constituting APRs (17–38) predicted using WALTZ, PASTA2, ANuPP, FishAmyloid, and MetAmyl (consensus) are highlighted as spheres. ChimeraX was used for visualization (Goddard et al. 2018)

Fig. 3

Various APR and aggregation propensity prediction tools

Fig. 4

All-atom simulation of peptide (VLVIY) assembly: a the initial setup of 105 peptides separated by 1 nm distance from each other and b the aggregated peptides after a simulation time of 50 ns. VMD was used for the visualization (Humphrey et al. 1996)

Fig. 5

Coarse-grained simulation of protein aggregation: a all-atom model, b Martini coarse-grained model (Marrink et al., 2007), and c aggregated structure obtained from coarse-grained simulation of α-synuclein protein. ChimeraX was used for visualization (Goddard et al. 2018)