Molecular dynamics simulations of proteins with chemically modified disulfide bonds

Proteins that are used as therapeutic drugs act in the extracellular microenvironment. They usually have a small number of intramolecular disulfide bonds to help maintain their tertiary structure in the vascular circulation. In general, most cysteine residues are part of a disulfide bond with free sulfhydrals being uncommon. We have studied whether the site-specific chemical reduction of disulfides and the incorporation of a 3-carbon methylene bridge between the cysteines in interferon-alpha 2a would change the structure of this protein. Bridging of both of the disulfide bonds of interferon-alpha 2a was studied using two different molecular simulation protocols: (1) molecular dynamics, and (2) stochastic dynamics. We have shown that the disulfide bonds in interferon-alpha 2a can be reduced and chemically modified without significantly altering the tertiary structure of the protein. This offers the novel possibility of chemically modifying therapeutically important proteins without affecting their biological properties.