Why it happens
Hydrophobic regions prefer contact with each other over contact with water. Near the pH of zero net charge, molecules no longer repel one another and association becomes easy. High concentration increases the frequency of encounters.
Once a few molecules associate they can template further association, which is why aggregation frequently accelerates once it starts.
Aggregation versus insolubility
Undissolved material is peptide that never entered solution; aggregate is peptide that did and then came out. The first may dissolve with time and gentle handling. The second usually will not, because the associated form is more stable than the dispersed one.
What makes it worse
- Vigorous shaking, which creates an air-liquid interface where proteins unfold
- Freeze-thaw cycling, which concentrates solutes as ice forms
- High concentration
- A solvent at the wrong pH
- Larger proteins, which have far more to unfold than a short peptide does
Detection
Visible haze or particles are the obvious signs, but aggregation can occur below the threshold of visibility and still affect an experiment.
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