The protein-folding problem is one of the great challenges of contemporary biology. Knowing how the sequence for a protein encodes its fold would open a world of possibilities to molecular sciences that would no doubt include insights into evolution, genetic diseases as well as the ability to engineer proteins with novel functions. While soluble protein folding has been investigated for decades, similar studies on membrane proteins are, by comparison, in their infancy.

 

We have overcome many technical obstacles to successfully determine the thermodynamic stability of several membrane proteins. In dissecting transmembrane protein stability, we have discovered a novel hydrophobicity scale, and – for the first time – we are able to derive sequence–structure–energy relationships for a set of membrane proteins. Our progress has been enabled using the transmembrane beta-barrel, a protein fold that is uniquely suited for these investigations. However, we show that our findings are applicable to transmembrane alpha-helical proteins as well.

 

We are further investigating the dynamical process undergone by proteins as they insert into membranes. How is it that a membrane protein can be trafficked to its native membrane and know to fold there? By conducting kinetic experiments of the folding pathway both in the presence and absence of cellular assembly factors, we are able to propose and are testing functional roles for biological chaperones.