(687e) Computer Simulation of Water Sorption On Flexible Protein Matrices

In the last two decades, protein therapeutics have emerged as the fastest-growing segment of the pharmaceutical industry, resulting in more than 200 new treatments for diseases such as AIDS, leukemia, melanoma, cystic fibrosis, and multiple sclerosis. Despite these advances, however, there remain a number of technical challenges in formulating and manufacturing new protein-based therapeutics. One of the most difficult tasks is to develop therapeutic formulations with long-term stability against the chemical degradation and protein aggregation processes that compromise the safety and efficacy of drugs that are stored in solution over long periods of time.

The standard approach for increasing the stability of protein therapeutics is to remove the biomolecules from their aqueous environment by incorporating them into vitrified solid materials using a process known as lyophilization or freeze-drying. In some cases, however, proteins often exhibit diminished therapeutic activity when they are reconstituted with water following storage in the glass state.  To understand this behavior, we use computer simulation to explore how proteins are affected by dehydration and subsequent rehydration. We demonstrate a new computational approach we have developed to study water sorption on protein crystals and powders, and show that this technique allows us, for the first time, to make rigorous contact with experimental measurements designed to probe the protein hydration process. We also show that we are able to go beyond the current capabilities of experimental techniques and investigate how changes in hydration level can give rise to microscopic mechanical stresses that may alter the structure and biological activity of some proteins.