AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures

Abstract

Protein aggregation underlies an increasing number of disorders and constitutes a major bottleneck in the development of therapeutic proteins. Our present understanding on the molecular determinants of protein aggregation has crystalized in a series of predictive algorithms to identify aggregation-prone sites. A majority of these methods rely only on sequence. Therefore, they find difficulties to predict the aggregation properties of folded globular proteins, where aggregation-prone sites are often not contiguous in sequence or buried inside the native structure. The AGGRESCAN3D (A3D) server overcomes these limitations by taking into account the protein structure and the experimental aggregation propensity scale from the well-established AGGRESCAN method. Using the A3D server, the identified aggregation-prone residues can be virtually mutated to design variants with increased solubility, or to test the impact of pathogenic mutations. Additionally, A3D server enables to take into account the dynamic fluctuations of protein structure in solution, which may influence aggregation propensity. This is possible in A3D Dynamic Mode that exploits the CABS-flex approach for the fast simulations of flexibility of globular proteins. The A3D server can be accessed at http://biocomp.chem.uw.edu.pl/A3D/.

Probing Medin Monomer Structure and its Amyloid Nucleation Using 13C-Direct Detection NMR in Combination with Structural Bioinformatics

“…Overall, the 185 ns structure following C-terminal detachment showed an increase in amyloid propensity compared to the starting structure with total score values of −2.00 and −29.87 respectively. This difference is larger than that between wild-type β2-microglobulin with low amyloid propensity at neutral pH (−73.54) and its well-characterised amyloidogenic ΔN6 variant which aggregates at neutral pH (−52.32)34. Furthermore, the total score of medin following C-terminal detachment (−2.00) is greater than that of the highly amyloidogenic β2-microglobulin variant ΔN6 (−52.32), suggesting an extremely high propensity for medin to self-assemble.…”

Variation Interpretation Predictors: Principles, Types, Performance, and Choice

“…Amino acid substitutions can increase the tendency of amyloidogenic proteins to aggregate. Methods for predicting the effect of amino acid substitutions on amyloidogenic proteins include AGGRESCAN [Conchillo‐Sole et al., ], PASTA2.0 [Walsh et al., ], TANGO [Fernandez‐Escamilla et al., ], and Aggrescan3D [Zambrano et al., ] (Supp. Table S1).…”

Understanding the mechanism of copurification of “difficult to remove” host cell proteins in rituximab biosimilar products

“…The mAb structure was analyzed to understand its surface stability in context to water solvent. Aggrescan3D (A3D) server detects the aggregation prone patches based on chemical nature of residue and solvents exposed surface area of given residue along with its neighbors . These aggregation prone detected patches are considered unstable on protein surface and prone to involvement in fibril formation.…”