Driving Forces for Nonnative Protein Aggregation and Approaches to Predict Aggregation-Prone Regions

Area of Science:

• Biochemistry
• Molecular Biology
• Protein Science

Background:

• Nonnative protein aggregation is a critical process where soluble proteins form insoluble aggregates.
• This process often involves partial unfolding and the formation of stable inter-protein contacts mediated by specific amino acid sequences known as aggregation-prone regions (APRs).
• Understanding the drivers of aggregation is crucial for various biological and medical contexts.

Purpose of the Study:

• To review the overall process and mechanistic drivers of nonnative protein aggregation.
• To summarize factors influencing the stabilization of protein aggregates by specific amino acid sequences.
• To survey publicly available algorithms for predicting aggregation-prone regions (APRs).

Main Methods:

• Literature review of nonnative protein aggregation mechanisms.
• Analysis of factors contributing to the stabilization of protein aggregates.
• Survey and categorization of computational algorithms for predicting aggregation-prone regions.

Main Results:

• Nonnative aggregation is initiated by conformational changes, exposing aggregation-prone regions (APRs).
• Multiple factors beyond APRs contribute to the stability and formation of protein aggregates.
• A range of algorithms exist for predicting APRs, though experimental validation remains a challenge.

Conclusions:

• Aggregation-prone regions (APRs) are key determinants in stabilizing nonnative protein aggregates.
• Predictive algorithms offer valuable tools, but experimental validation is essential for accuracy.
• Further research is needed to fully elucidate the complex interplay of factors driving protein aggregation.