Optimal design of thermally stable proteins

Motivation: For many biotechnological purposes, it is desirable to redesign proteins to be more structurally and functionally stable at higher temperatures. For example, chemical reactions are intrinsically faster at higher temperatures, so using enzymes that are stable at higher temperatures would lead to more efficient industrial processes. We describe an innovative and computationally efficient method called Improved Configurational Entropy (ICE), which can be used to redesign a protein to be more thermally stable (i.e. stable at high temperatures). This can be accomplished by systematically modifying the amino acid sequence via local structural entropy (LSE) minimization. The minimization problem is modeled as a shortest path problem in an acyclic graph with nonnegative weights and is solved efficiently using Dijkstra's method. Contact: mitchell@biochem.wisc.edu

[1]  Robert E. Tarjan,et al.  Fibonacci heaps and their uses in improved network optimization algorithms , 1984, JACM.

[2]  Robert E. Tarjan,et al.  Fibonacci heaps and their uses in improved network optimization algorithms , 1987, JACM.

[3]  John Beidler,et al.  Data Structures and Algorithms , 1996, Wiley Encyclopedia of Computer Science and Engineering.

[4]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[5]  C. Vieille,et al.  Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability , 2001, Microbiology and Molecular Biology Reviews.

[6]  M. Lehmann,et al.  Engineering proteins for thermostability: the use of sequence alignments versus rational design and directed evolution. , 2001, Current opinion in biotechnology.

[7]  A. Keith Dunker,et al.  DISORDER AND FLEXIBILITY IN PROTEIN STRUCTURE AND FUNCTION , 2000 .

[8]  L. Serrano,et al.  Sequence determinants of amyloid fibril formation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Schoemaker,et al.  Dispelling the Myths--Biocatalysis in Industrial Synthesis , 2003, Science.

[10]  V. Eijsink,et al.  Rational engineering of enzyme stability. , 2004, Journal of biotechnology.

[11]  Julie C. Mitchell,et al.  Singular hydrophobicity patterns and net charge: a mesoscopic principle for protein aggregation/folding , 2004 .

[12]  Chenhsiung Chan,et al.  Relationship between local structural entropy and protein thermostabilty , 2004, Proteins.

[13]  B. Stoddard,et al.  Computational Thermostabilization of an Enzyme , 2005, Science.

[14]  V. Eijsink,et al.  Directed evolution of enzyme stability. , 2005, Biomolecular engineering.

[15]  A. Esteras-Chopo,et al.  The amyloid stretch hypothesis: recruiting proteins toward the dark side. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Couñago,et al.  In vivo molecular evolution reveals biophysical origins of organismal fitness. , 2006, Molecular cell.

[17]  D. Baker,et al.  The 3D profile method for identifying fibril-forming segments of proteins. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Michail Yu. Lobanov,et al.  Prediction of Amyloidogenic and Disordered Regions in Protein Chains , 2006, PLoS Comput. Biol..

[19]  Pernilla Turner,et al.  Potential and utilization of thermophiles and thermostable enzymes in biorefining , 2007, Microbial cell factories.

[20]  Geoffrey K. Hom,et al.  Full-sequence computational design and solution structure of a thermostable protein variant. , 2007, Journal of molecular biology.

[21]  P. Romero,et al.  Natively Disordered Proteins , 2008, Applied bioinformatics.

[22]  R. Bannen,et al.  Bioinformatic method for protein thermal stabilization by structural entropy optimization , 2008, Proceedings of the National Academy of Sciences.

[23]  H. Leemhuis,et al.  Directed evolution of enzymes: Library screening strategies , 2009, IUBMB life.