Packing of apolar side chains enables accurate design of highly stable membrane proteins

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6434; pp. 1418 - 1423
• Main Authors: Mravic, Marco, Thomaston, Jessica L, Tucker, Maxwell, Solomon, Paige E, Liu, Lijun, DeGrado, William F
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 29.03.2019
• Subjects: Amino Acid Sequence; Amino acids; Calcium-Binding Proteins - chemistry; Chains; Complementarity; Design; Disruption; Folding; Hydrogen bonding; Hydrogen bonds; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Informatics; Interfaces; Lipids; Membrane proteins; Membrane Proteins - chemistry; Membranes; Models, Molecular; Molecular Dynamics Simulation; Packing; Phospholamban; Protein Engineering - methods; Protein Folding; Protein Stability; Protein Structure, Secondary; Proteins; Proteomes; Redesign; Stability
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aav7541

The features that stabilize the structures of membrane proteins remain poorly understood. Polar interactions contribute modestly, and the hydrophobic effect contributes little to the energetics of apolar side-chain packing in membranes. Disruption of steric packing can destabilize the native folds of membrane proteins, but is packing alone sufficient to drive folding in lipids? If so, then membrane proteins stabilized by this feature should be readily designed and structurally characterized-yet this has not been achieved. Through simulation of the natural protein phospholamban and redesign of variants, we define a steric packing code underlying its assembly. Synthetic membrane proteins designed using this code and stabilized entirely by apolar side chains conform to the intended fold. Although highly stable, the steric complementarity required for their folding is surprisingly stringent. Structural informatics shows that the designed packing motif recurs across the proteome, emphasizing a prominent role for precise apolar packing in membrane protein folding, stabilization, and evolution.