Evolutionarily conserved linkage between enzyme fold, flexibility, and catalysis.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2003]-

Evolution, Molecular*; Enzymes/*chemistry ; Enzymes/*metabolism; Catalysis ; Computer Simulation ; Cyclophilins ; Humans ; Models, Molecular ; Oxidoreductases/chemistry ; Oxidoreductases/metabolism ; Peptidylprolyl Isomerase/chemistry ; Peptidylprolyl Isomerase/metabolism ; Protein Folding ; Ribonucleases/chemistry ; Ribonucleases/metabolism

Proteins are intrinsically flexible molecules. The role of internal motions in a protein's designated function is widely debated. The role of protein structure in enzyme catalysis is well established, and conservation of structural features provides vital clues to their role in function. Recently, it has been proposed that the protein function may involve multiple conformations: the observed deviations are not random thermodynamic fluctuations; rather, flexibility may be closely linked to protein function, including enzyme catalysis. We hypothesize that the argument of conservation of important structural features can also be extended to identification of protein flexibility in interconnection with enzyme function. Three classes of enzymes (prolyl-peptidyl isomerase, oxidoreductase, and nuclease) that catalyze diverse chemical reactions have been examined using detailed computational modeling. For each class, the identification and characterization of the internal protein motions coupled to the chemical step in enzyme mechanisms in multiple species show identical enzyme conformational fluctuations. In addition to the active-site residues, motions of protein surface loop regions (>10 Å away) are observed to be identical across species, and networks of conserved interactions/residues connect these highly flexible surface regions to the active-site residues that make direct contact with substrates. More interestingly, examination of reaction-coupled motions in non-homologous enzyme systems (with no structural or sequence similarity) that catalyze the same biochemical reaction shows motions that induce remarkably similar changes in the enzyme-substrate interactions during catalysis. The results indicate that the reaction-coupled flexibility is a conserved aspect of the enzyme molecular architecture. Protein motions in distal areas of homologous and non-homologous enzyme systems mediate similar changes in the active-site enzyme-substrate interactions, thereby impacting the mechanism of catalyzed chemistry. These results have implications for understanding the mechanism of allostery, and for protein engineering and drug design.
Competing Interests: The authors have declared that no competing interests exist.

Science. 2004 Jan 9;303(5655):186-95. (PMID: 14716003)
Biochemistry. 2005 Dec 27;44(51):16835-43. (PMID: 16363797)
J Comput Biol. 2010 Mar;17(3):309-24. (PMID: 20377447)
Science. 2008 Oct 17;322(5900):438-42. (PMID: 18927392)
Gene. 2008 Oct 1;422(1-2):7-13. (PMID: 18577430)
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80. (PMID: 7984417)
Annu Rev Biochem. 2006;75:519-41. (PMID: 16756501)
Chembiochem. 2005 Apr;6(4):590-600. (PMID: 15812782)
J Comput Chem. 2005 Dec;26(16):1668-88. (PMID: 16200636)
Proteins. 2004 Aug 15;56(3):449-63. (PMID: 15229879)
J Chem Phys. 2004 Apr 22;120(16):7755-60. (PMID: 15267689)
Chem Rev. 2006 Aug;106(8):3055-79. (PMID: 16895318)
PLoS One. 2011 Jan 28;6(1):e15827. (PMID: 21297978)
Science. 2006 Sep 15;313(5793):1638-42. (PMID: 16973882)
Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 2000 Dec;62(6 Pt B):8438-48. (PMID: 11138145)
Biochemistry. 2000 May 30;39(21):6267-74. (PMID: 10828939)
Biochemistry. 2002 Jul 2;41(26):8221-8. (PMID: 12081470)
Front Biosci. 2004 Sep 01;9:3453-78. (PMID: 15353370)
Chem Rev. 2006 May;106(5):1737-56. (PMID: 16683752)
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17359-64. (PMID: 19805169)
J Am Chem Soc. 2003 Dec 10;125(49):15028-38. (PMID: 14653737)
Biochemistry. 2006 Feb 7;45(5):1383-92. (PMID: 16445280)
Nat Struct Mol Biol. 2006 Mar;13(3):184-5; discussion 185. (PMID: 16518382)
J Phys Chem B. 2010 Dec 9;114(48):15985-90. (PMID: 21077591)
Protein Sci. 2008 May;17(5):918-29. (PMID: 18369194)
J Mol Biol. 2007 Jan 26;365(4):1143-62. (PMID: 17113106)
Biochemistry. 2004 Jan 20;43(2):374-83. (PMID: 14717591)
Nature. 2009 Dec 3;462(7273):669-73. (PMID: 19956261)
J Mol Biol. 2007 Apr 13;367(5):1370-81. (PMID: 17316687)
Nat Struct Biol. 2003 Jun;10(6):475-81. (PMID: 12730686)
Biochemistry. 1997 Jan 21;36(3):586-603. (PMID: 9012674)
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2794-9. (PMID: 11867722)
Proteins. 2002 Aug 15;48(3):487-96. (PMID: 12112673)
Chem Biol. 2004 Aug;11(8):1037-42. (PMID: 15324804)
Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14408-13. (PMID: 15448207)
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11981-6. (PMID: 17615241)
Proc Natl Acad Sci U S A. 1958 Feb;44(2):98-104. (PMID: 16590179)
Nature. 2007 Dec 6;450(7171):913-6. (PMID: 18026087)
Angew Chem Int Ed Engl. 2005 May 30;44(22):3394-9. (PMID: 15912573)
J Biol Chem. 1998 Oct 9;273(41):26257-60. (PMID: 9756847)
Nature. 2005 Nov 3;438(7064):117-21. (PMID: 16267559)
J Mol Biol. 1999 Jan 22;285(3):1209-33. (PMID: 9918722)
Curr Opin Chem Biol. 2006 Oct;10(5):492-7. (PMID: 16935022)
Biochemistry. 2008 Mar 18;47(11):3317-21. (PMID: 18298083)
Biochemistry. 2010 Oct 26;49(42):9078-88. (PMID: 20795731)
J Am Chem Soc. 2005 Sep 21;127(37):12997-3006. (PMID: 16159295)
J Am Chem Soc. 2005 Nov 2;127(43):15248-56. (PMID: 16248667)
Annu Rev Biochem. 2001;70:209-46. (PMID: 11395407)
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):6980-5. (PMID: 12756296)
Biochemistry. 2006 Feb 28;45(8):2636-47. (PMID: 16489757)
Science. 1999 Oct 8;286(5438):295-9. (PMID: 10514373)
Chem Rev. 2006 Aug;106(8):3080-94. (PMID: 16895319)
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6807-12. (PMID: 15811945)
J Biol Chem. 2004 Nov 5;279(45):46995-7002. (PMID: 15333636)
Biochemistry. 2009 Aug 4;48(30):7160-8. (PMID: 19588901)
Science. 2003 Aug 29;301(5637):1196-202. (PMID: 12947189)
J Phys Chem B. 2010 Jun 3;114(21):7371-82. (PMID: 20455590)
J Am Chem Soc. 2006 Aug 2;128(30):9766-72. (PMID: 16866533)
J Am Chem Soc. 2002 Apr 3;124(13):3270-6. (PMID: 11916410)
Biophys J. 2000 Apr;78(4):2093-106. (PMID: 10733987)
J Phys Chem B. 2006 Feb 9;110(5):2435-41. (PMID: 16471835)
Nat Chem Biol. 2009 Aug;5(8):543-50. (PMID: 19620995)
J Phys Chem B. 2009 Dec 31;113(52):16669-80. (PMID: 19908896)
Science. 1988 Oct 28;242(4878):533-40. (PMID: 3051385)
Microb Cell Fact. 2006 Jan 12;5:2. (PMID: 16409630)
Adv Enzymol Relat Areas Mol Biol. 1975;43:219-410. (PMID: 892)
Chem Rev. 2006 Aug;106(8):3210-35. (PMID: 16895325)
Biochemistry. 2003 Nov 25;42(46):13558-75. (PMID: 14622003)
Biochemistry. 2007 Dec 25;46(51):14878-88. (PMID: 18052202)
Biochemistry. 2002 May 14;41(19):6072-81. (PMID: 11994002)
Science. 2002 Feb 22;295(5559):1520-3. (PMID: 11859194)
Cell. 1997 Jun 13;89(6):875-86. (PMID: 9200606)
Nat Chem Biol. 2009 Aug;5(8):551-8. (PMID: 19620996)
Biochemistry. 2004 Aug 24;43(33):10605-18. (PMID: 15311922)
Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15753-8. (PMID: 17032759)
Biochemistry. 2007 Feb 13;46(6):1466-76. (PMID: 17279612)
Proc Natl Acad Sci U S A. 1984 Jan;81(2):444-8. (PMID: 6582500)
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1373-8. (PMID: 20080605)

0 (Enzymes)
EC 1.- (Oxidoreductases)
EC 3.1.- (Ribonucleases)
EC 5.2.1.- (Cyclophilins)
EC 5.2.1.8 (Peptidylprolyl Isomerase)

Date Created: 20111117 Date Completed: 20120517 Latest Revision: 20211021

20231215

PMC3210774

10.1371/journal.pbio.1001193

22087074