Keeping dry and crossing membranes

Abstract

Water sustains life but also imposes constraints on what life should be like. Its high dipole moment, proton donor-acceptor dual nature and rotational freedom make it a powerful former of hydrogen bonds. In solu- ble proteins, this property places stringent constraints on the way proteins interact (1-4) and fold (5). I argue here that the manipulation of intramolecularly underdehydrated or underwrapped electrostatic interactions in proteins can be exploited in engineering strategies to create molecules with an enhanced ability to traverse biological membranes, with potential implications for oral delivery of peptide-based drugs.