Computational De Novo Design and Characterization of a Four-Helix Bundle Protein that Selectively Binds a Nonbiological Cofactor

摘要

De novo design tests current understanding of metalloproteins and offers the potential to construct novel biomaterials,such as catalysts and bioelectrochemical devices.The use of nonbio-logical cofactors in these efforts offers the possibility of creating proteins with unusual properties.We have developed computational design methodology to derive a unique protein framework for a specified cofactor of interest as an alternative to re-engineering natural protein scaffolds.Selective cofactor recognition is a hallmark of achieving this goal and a significant challenge,especially in the absence of covalent attachment.Previously designed heme proteins bound various metalloporphyrins with relatively low specificity,which is likely attributable to molten globule character.In contrast,natural proteins generally bind cofactors in well-structured environments with precisely positioned amino acid side chains.Here,we report the complete de novo design of a nativelike protein that selectively binds a nonbiological cofactor.