Coarse-grained free energy functions for studying protein conformational changes: a double-well network model.
In this work, a double-well network model (DWNM) is presented for generating a coarse-grained free energy function that can be used to study the transition between reference conformational states of a protein molecule. Compared to earlier work that uses a single, multidimensional double-well potential to connect two conformational states, the DWNM uses a set of interconnected double-well potentials for this purpose. The DWNM free energy function has multiple intermediate states and saddle points, and is hence a "rough" free energy landscape. In this implementation of the DWNM, the free energy function is reduced to an elastic-network model representation near the two reference states. The effects of free energy function roughness on the reaction pathways of protein conformational change is demonstrated by applying the DWNM to the conformational changes of two protein systems: the coil-to-helix transition of the DB-loop in G-actin and the open-to-closed transition of adenylate kinase. In both systems, the rough free energy function of the DWNM leads to the identification of distinct minimum free energy paths connecting two conformational states. These results indicate that while the elastic-network model captures the low-frequency vibrational motions of a protein, the roughness in the free energy function introduced by the DWNM can be used to characterize the transition mechanism between protein conformations.
Chu
Jhih-Wei
JW
Center for Biophysical Modeling and Simulation and Department of Chemistry, University of Utah, Salt Lake City, Utah, USA.
Voth
Gregory A
GA
D003198:Computer Simulation; D004735:Energy Transfer; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000648:ultrastructure*
D011506:Proteins
Biochim Biophys Acta. 2000 Aug 30;1460(1):157-65
10984597
J Biol Chem. 1992 Jun 15;267(17):11661-4
1318297
J Chem Phys. 2004 Jun 15;120(23):10880-9
15268118
Bioessays. 2001 Aug;23(8):725-32
11494321
Micron. 2002;33(4):385-97
11814877
Biophys J. 2002 Dec;83(6):3357-70
12496103
J Biol Chem. 2003 Sep 5;278(36):34172-80
12813032
Pharmacol Ther. 1996;70(3):215-56
8888067
Nature. 1994 May 19;369(6477):248-51
7710478
J Struct Biol. 2007 Mar;157(3):606-15
17029846
Curr Opin Neurobiol. 2005 Jun;15(3):289-95
15922585
J Mol Biol. 2004 Apr 2;337(4):985-99
15033365
Q Rev Biophys. 2005 Nov;38(4):405-10
16934172
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7664-9
16682636
J Mol Biol. 1999 Jan 22;285(3):1023-37
9887265
Int J Pept Protein Res. 1975;7(6):445-59
1201909
Nature. 1990 Oct 18;347(6294):631-9
2215695
J Mol Biol. 2005 Sep 30;352(4):807-22
16139299
Biochemistry. 1996 May 21;35(20):6425-37
8639589
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18939-44
17135353
Phys Rev Lett. 1996 Aug 26;77(9):1905-1908
10063201
J Mol Biol. 1993 Jul 20;232(2):334-41
8345515
Chem Rev. 2006 Aug;106(8):3055-79
16895318
Curr Opin Struct Biol. 2005 Apr;15(2):151-6
15837172
J Struct Biol. 2004 Sep;147(3):315-26
15450300
Annu Rev Biophys Biomol Struct. 1995;24:85-116
7663132
J Struct Biol. 2004 Sep;147(3):291-301
15450298
Phys Chem Chem Phys. 2006 Dec 21;8(47):5543-8
17136269
Biophys J. 2007 Feb 1;92(3):731-43
17028142
EMBO J. 2006 May 3;25(9):1967-76
16601695
Curr Opin Struct Biol. 2005 Apr;15(2):144-50
15837171
J Mol Graph Model. 2002 Oct;21(2):151-60
12398345
Nat Biotechnol. 2003 Nov;21(11):1387-95
14595367
Protein Sci. 2002 Oct;11(10):2351-61
12237457
Adv Protein Chem. 1998;51:185-253
9615171
Science. 2001 Jul 27;293(5530):708-11
11474115
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12570-5
14566052
Biophys J. 2006 Mar 1;90(5):1572-82
16361345
J Mol Biol. 2005 Feb 25;346(3):745-59
15713460
Curr Opin Struct Biol. 2005 Oct;15(5):586-92
16143512
Cell. 2002 May 3;109(3):275-82
12015977
Biophys J. 2006 Nov 15;91(10):3797-804
16935954
Biochim Biophys Acta. 2000 Mar 16;1478(1):138-51
10719182
Nature. 1990 Sep 6;347(6288):44-9
2395461
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6679-85
15870208
Biophys Chem. 1996 Apr 16;59(3):329-39
8672720
J Chem Theory Comput. 2006;2(3):667-673
19461947
Proteins. 1995 Mar;21(3):167-95
7784423
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13111-6
16135566
Biophys J. 2005 May;88(5):3109-17
15722427
J Phys Chem B. 2005 Apr 14;109(14):6688-93
16851751
Nat Struct Mol Biol. 2006 Sep;13(9):831-8
16906160
J Mol Biol. 1992 Oct 20;227(4):1043-53
1433285
J Inorg Biochem. 2000 Nov;82(1-4):1-7
11132615
Annu Rev Phys Chem. 2002;53:291-318
11972010
Science. 1995 Mar 31;267(5206):1924-35
17770101
Fold Des. 1997;2(3):173-81
9218955
J Am Chem Soc. 2001 Sep 5;123(35):8638-9
11525689
Nat Struct Biol. 2000 Jan;7(1):34-8
10625424
Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11844-9
16877541
Structure. 2005 Dec;13(12):1755-63
16338404
Annu Rev Biophys Bioeng. 1983;12:183-210
6347038
J Chem Phys. 2005 Oct 1;123(13):134105
16223273
Nature. 1990 Sep 6;347(6288):37-44
2395459
Science. 2006 Apr 14;312(5771):217-24
16614209
J Phys Chem B. 2005 Feb 10;109(5):1959-69
16851180
Annu Rev Biophys Biomol Struct. 2006;35:115-33
16689630
Adv Protein Chem. 2000;53:87-152
10751944
J Biol Chem. 1995 May 12;270(19):11437-44
7744781
J Mol Biol. 1992 Mar 5;224(1):159-77
1548697
Biophys J. 2007 Aug 15;93(4):1277-83
17526584
Drug Discov Today. 2006 Mar;11(5-6):191-202
16580596
Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6369-72
8327519
Structure. 2005 Mar;13(3):363-72
15766537
Phys Rev Lett. 2000 Sep 11;85(11):2404-7
10978021
Mol Cell. 2007 May 11;26(3):449-57
17499050
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1274-9
11818549
Physiol Rev. 1982 Apr;62(2):672-737
6280220
Adv Protein Chem. 1995;47:83-229
8561052
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):29-34
9874766
Prog Biophys Mol Biol. 2002 May-Jul;79(1-3):1-43
12225775
Structure. 2005 Mar;13(3):373-80
15766538
Structure. 1996 Feb 15;4(2):147-56
8805521
J Phys Chem B. 2006 Nov 30;110(47):24121-37
17125384