Proton transfer function of carbonic anhydrase: Insights from QM/MM simulations.
Recent QM/MM analyses of proton transfer function of human carbonic anhydrase II (CAII) are briefly reviewed. The topics include a preliminary analysis of nuclear quadrupole coupling constant calculations for the zinc ion and more detailed analyses of microscopic pK(a) of the zinc-bound water and free energy profile for the proton transfer. From a methodological perspective, our results emphasize that performing sufficient sampling is essential to the calculation of all these quantities, which reflects the well solvated nature of CAII active site. From a mechanistic perspective, our analyses highlight the importance of electrostatics in shaping the energetics and kinetics of proton transfer in CAII for its function. We argue that once the pK(a) for the zinc-bound water is modulated to be in the proper range (approximately 7.0), proton transfer through a relatively well solvated cavity towards/from the protein surface (His64) does not require any major acceleration. Therefore, although structural details like the length of the water wire between the donor and acceptor groups still may make a non-negligible contribution, our computational results and the framework of analysis suggest that the significance of such "fine-tuning" is likely secondary to the modulation of pK(a) of the zinc-bound water. We encourage further experimental analysis with mutation of (charged) residues not in the immediate neighborhood of the zinc ion to quantitatively test this electrostatics based framework; in particular, Phi analysis based on these mutations may shed further light into the relative importance of the classical Grotthus mechanism and the "proton hole" pathway that we have proposed recently for CAII.
Riccardi
Demian
D
Department of Biochemistry, University of Wisconsin, Madison, Madison, WI 53706, USA.
Yang
Shuo
S
Cui
Qiang
Q
D000818:Animals; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D017136:Ion Transport; D011522:Protons; D045663:Quantum Dots; D014867:Water
D011522:Protons; D014867:Water; D002256:Carbonic Anhydrases
J Am Chem Soc. 2006 Dec 20;128(50):16302-11
17165785
Adv Protein Chem. 2003;66:249-313
14631821
J Am Chem Soc. 2008 May 14;130(19):6224-30
18410102
J Phys Chem B. 2008 Jul 17;112(28):8387-97
18540669
Biochemistry. 1991 Sep 24;30(38):9153-60
1909891
Biochemistry. 2007 Mar 27;46(12):3803-13
17330962
J Am Chem Soc. 2005 Mar 2;127(8):2370-1
15724973
Biochim Biophys Acta. 2006 Aug;1757(8):942-68
16905113
J Mol Biol. 1992 Oct 20;227(4):1192-204
1433293
Eur J Biochem. 1993 Feb 1;211(3):821-7
8436138
J Phys Chem B. 2005 May 12;109(18):9082-95
16852081
J Phys Chem A. 2007 Jul 5;111(26):5751-5
17385847
Science. 2004 Jan 9;303(5655):186-95
14716003
J Comput Chem. 2003 Apr 15;24(5):565-81
12632471
J Am Chem Soc. 2009 May 27;131(20):7064-78
19405533
Curr Opin Struct Biol. 2007 Oct;17(5):617-22
17964133
J Phys Chem B. 2005 Sep 22;109(37):17715-33
16853267
Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
9944570
Proteins. 1993 Sep;17(1):93-106
7901850
J Mol Biol. 1992 Apr 5;224(3):771-82
1569556
Proteins. 2006 Sep 1;64(4):829-44
16779836
J Am Chem Soc. 2004 Apr 14;126(14):4735-9
15070393
Proteins. 1998 Oct 1;33(1):119-34
9741850
J Phys Chem A. 2007 Oct 25;111(42):10861-73
17914769
Chembiochem. 2001 Mar 2;2(3):190-8
11828444
Biochemistry. 2008 Feb 26;47(8):2369-78
18247480
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
Annu Rev Phys Chem. 2008;59:573-601
18393679
Acc Chem Res. 2007 Aug;40(8):669-75
17550224
J Phys Chem A. 2006 Jan 19;110(2):548-63
16405327
J Phys Chem B. 2009 Feb 5;113(5):1253-72
19055405
J Phys Chem B. 2006 Apr 6;110(13):6458-69
16570942
J Am Chem Soc. 2004 Nov 10;126(44):14668-77
15521787
Angew Chem Int Ed Engl. 2009;48(7):1198-229
19173328
J Am Chem Soc. 2009 Jun 10;131(22):7598-608
19438233
J Am Chem Soc. 2001 Jun 27;123(25):5861-6
11414818
Nature. 1991 Mar 14;350(6314):121-4
2005961
Phys Rev A Gen Phys. 1988 Sep 15;38(6):3098-3100
9900728
Biochemistry. 2005 Feb 1;44(4):1097-105
15667203
Biochim Biophys Acta. 2000 May 12;1458(1):88-103
10812026
Methods Enzymol. 1995;249:479-503
7791624
J Comput Chem. 2007 Jul 15;28(9):1485-1502
17334987
J Chem Phys. 2005 Jul 1;123(1):014905
16035867
Biochemistry. 2007 Mar 20;46(11):2938-47
17319695
J Chem Theory Comput. 2007 Mar;3(2):390-406
19079734
Acc Chem Res. 2006 Feb;39(2):143-50
16489734
J Am Chem Soc. 2007 Jul 25;129(29):9192-200
17595082
J Phys Chem A. 2007 Jul 5;111(26):5703-11
17506534
Phys Chem Chem Phys. 2005 Aug 21;7(16):3070-9
16186912
Biochemistry. 2009 Mar 24;48(11):2468-85
19243111
Adv Protein Chem. 2003;66:315-72
14631822
J Am Chem Soc. 2008 Sep 24;130(38):12671-9
18761443
Structure. 2004 Jan;12(1):65-74
14725766