It is hard to wrap one’s head around the concept of underwrapping (no pun intended) but it is not so intimidating (underwrap = expose to solvent). Ariel Fernandez uses it to describe peptide structures. He applies a variety of metrics to arrange the corresponding peptide molecules on the spectrum of toxicity (and many other properties such as cell permeability). In his Nature Biotechnology commentary several years ago, Ariel has made some compelling arguments pointing to a correlation between properties such as toxicity of a peptide and the extent of hydrogen bond accessibility. There are many other properties described in this work as well.
For instance, the worst wrapper of hydrogen bonds in the entire protein database is the peptide toxin isolated from green mamba venom.
Given the amount of current interest in macrocycles made out of amino acids, people should pay special attention to how hydrogen bonds are “shielded”… A molecule must also keep its hydrogen bonds dry if it wants to cross the cell membrane. This is another lesson emerging from Ariel’s work.