Controlling complexity and water penetration in functional de novo protein design.

Natural proteins are complex, and the engineering elements that support function and catalysis are obscure. Simplified synthetic protein scaffolds offer a means to avoid such complexity, learn the underlying principles behind the assembly of function and render the modular assembly of enzymatic function a tangible reality. A key feature of such protein design is the control and exclusion of water access to the protein core to provide the low-dielectric environment that enables enzymatic function. Recent successes in de novo protein design have illustrated how such control can be incorporated into the design process and have paved the way for the synthesis of nascent enzymatic activity in these systems.

[1]  A. Wand,et al.  The HP-1 maquette: from an apoprotein structure to a structured hemoprotein designed to promote redox-coupled proton exchange. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Julia M. Shifman,et al.  Functionalized de novo designed proteins: mechanism of proton coupling to oxidation/reduction in heme protein maquettes. , 1998, Biochemistry.

[3]  W. Jencks.  Catalysis in chemistry and enzymology , 1969 .

[4]  J. Wang.  HEMOGLOBIN STUDIES. II. A SYNTHETIC MATERIAL WITH HEMOGLOBIN-LIKE PROPERTY1 , 1958 .

[5]  W. Jencks,et al.  Binding energy, specificity, and enzymic catalysis: the circe effect. , 2006, Advances in enzymology and related areas of molecular biology.

[6]  A. Wand,et al.  Global topology & stability and local structure & dynamics in a synthetic spin-labeled four-helix bundle protein. , 1997, Biochemistry.

[7]  K N Houk,et al.  Quantum mechanical design of enzyme active sites. , 2008, The Journal of organic chemistry.

[8]  J. Hoch,et al.  Characterization of the structural properties of .alpha.1B, a peptide designed to form a four-helix bundle , 1992 .

[9]  Christopher C. Moser,et al.  Design and synthesis of multi-haem proteins , 1994, Nature.

[10]  Julia M. Shifman,et al.  Heme redox potential control in de novo designed four-alpha-helix bundle proteins. , 2000, Biochemistry.

[11]  H. Muller.  THE RELATION OF RECOMBINATION TO MUTATIONAL ADVANCE. , 1964, Mutation research.

[12]  R. H.J.MULLE.  THE RELATION OF RECOMBINATION TO MUTATIONAL ADVANCE , 2002 .

[13]  C. Darwin.  The Origin of Species by Means of Natural Selection, Or, The Preservation of Favoured Races in the Struggle for Life , 1859 .

[14]  J. Wang,et al.  Hemoglobin Studies. I. The Combination of Carbon Monoxide with Hemoglobin and Related Model Compounds , 1958 .

[15]  Eric A. Althoff,et al.  Kemp elimination catalysts by computational enzyme design , 2008, Nature.

[16]  D. Boehr,et al.  The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis , 2006, Science.

[17]  J. Lecomte,et al.  Structural and thermodynamic consequences of b heme binding for monomeric apoglobins and other apoproteins. , 2007, Gene.

[18]  E. Corey,et al.  On the failure of de novo-designed peptides as biocatalysts. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Dutton,et al.  Design of amphiphilic protein maquettes: controlling assembly, membrane insertion, and cofactor interactions. , 2005, Biochemistry.

[20]  J. Dawson,et al.  Heme-Containing Oxygenases. , 1996, Chemical reviews.

[21]  C. Sunderland,et al.  Functional analogues of cytochrome c oxidase, myoglobin, and hemoglobin. , 2004, Chemical reviews.

[22]  T M Handel,et al.  Metal ion-dependent modulation of the dynamics of a designed protein. , 1993, Science.

[23]  F. Rabanal,et al.  Proof of principle in a de novo designed protein maquette: an allosterically regulated, charge-activated conformational switch in a tetra-alpha-helix bundle. , 2001, Biochemistry.

[24]  D. J. Kiviet,et al.  Empirical fitness landscapes reveal accessible evolutionary paths , 2007, Nature.

[25]  W. DeGrado,et al.  How do helix–helix interactions help determine the folds of membrane proteins? Perspectives from the study of homo‐oligomeric helical bundles , 2003, Protein science : a publication of the Protein Society.

[26]  D. Engelman,et al.  Motifs of serine and threonine can drive association of transmembrane helices. , 2002, Journal of molecular biology.

[27]  W. DeGrado,et al.  Synthetic amphiphilic peptide models for protein ion channels. , 1988, Science.

[28]  B. R. Gibney,et al.  X-ray structure of a maquette scaffold. , 2003, Journal of molecular biology.

[29]  Eric A. Althoff,et al.  De Novo Computational Design of Retro-Aldol Enzymes , 2008, Science.

[30]  Julia M. Shifman,et al.  Heme Redox Potential Control in de Novo Designed Four-R-Helix Bundle Proteins † , 2022 .

[31]  A. Wand,et al.  Hydrophobic modulation of heme properties in heme protein maquettes. , 2001, Biochemistry.

[32]  D. Hilvert.  Critical analysis of antibody catalysis. , 2000, Annual review of biochemistry.

[33]  L. Regan,et al.  Characterization of a helical protein designed from first principles. , 1988, Science.

[34]  R. Wolfenden.  Waterlogged molecules. , 1983, Science.

[35]  Kevin M. Smith,et al.  Nativelike structure in designed four alpha-helix bundles driven by buried polar interactions. , 2006, Journal of the American Chemical Society.

[36]  L. Baltzer,et al.  Emerging principles of de novo catalyst design. , 2001, Current opinion in biotechnology.

[37]  A. Warshel,et al.  Electrostatic basis for enzyme catalysis. , 2006, Chemical reviews.