Computational Design To Reduce Conformational Flexibility and Aggregation Rates of an Antibody Fab Fragment.

Computationally guided semirational design has significant potential for improving the aggregation kinetics of protein biopharmaceuticals. While improvement in the global conformational stability can stabilize proteins to aggregation under some conditions, previous studies suggest that such an approach is limited, because thermal transition temperatures ( T) and the fraction of protein unfolded ( f) tend to only correlate with aggregation kinetics where the protein is incubated at temperatures approaching the T. This is because under these conditions, aggregation from globally unfolded protein becomes dominant.