Diversity of function-related conformational changes in proteins: coordinate uncertainty, fragment rigidity, and stability.
It was found that the variety of function-related conformational changes ("movements") in proteins is beyond the earlier simple classifications. Here we offer biochemists a more comprehensive, transparent, and easy-to-use approach allowing a detailed and accurate interpretation of such conformational changes. It makes possible a more multifaceted characterization of protein flexibility via identification of rigidly and nonrigidly repositioned fragments, stable and nonstable fragments, and domain and nondomain repositioning. "Coordinate uncertainty thresholds" derived from computed differences between independently determined coordinates of the same molecules are used as the criteria for conformational identity. "Identical" rigid substructures are localized in the distance difference matrices (DDMs). A sequence of simple transformations determines whether a structural change occurs by rigid-body movements of fragments or largely through non-rigid-body deformations. We estimate the stability of protein fragments and compare stable and rigidly moving fragments. The motions computed with the coarse-grained elastic networks are also compared to those of their DDM analogues. We study and suggest a classification for 17 structural pairs, differing in their functional states. For five of the 17 proteins, conformational change cannot be accomplished by rigid-body transformations and requires significant non-rigid-body deformations. Stable fragments rarely coincide with rigidly moving fragments and often disagree with the CATH identifications of domains. Almost all monomeric apo chains, containing stable fragments and/or domains, indicate instability of the entire molecule, suggesting the importance of fragments and domains motions prior to stabilization by substrate binding or crystallization. Notably, kinases exhibit the greatest extent of nonrigidity among the proteins investigated.
Rashin
Alexander A
AA
BioChemComp Inc., 543 Sagamore Avenue, Teaneck, New Jersey 07666, USA. Alexander_Rashin@hotmail.com
Rashin
Abraham H L
AH
Jernigan
Robert L
RL
D003460:Crystallization; D046911:Macromolecular Substances / Q000737:chemistry*; D019563:Mechanics; D008968:Molecular Conformation; D009038:Motion; D055585:Physical Phenomena; D011506:Proteins / Q000737:chemistry*; D035501:Uncertainty
D046911:Macromolecular Substances; D011506:Proteins
Methods Biochem Anal. 2003;44:365-85
12647395
Acta Crystallogr D Biol Crystallogr. 2002 Jun;58(Pt 6 Pt 2):1002-7
12037302
Biopolymers. 1984 Aug;23(8):1605-20
6466778
Methods Enzymol. 2000;323:31-62
10944746
Prog Biophys Mol Biol. 1983;42(1):21-78
6353481
Cell. 1997 May 16;89(4):545-53
9160746
J Comput Chem. 2004 Nov 30;25(15):1849-57
15376254
Biophys J. 2002 Sep;83(3):1620-30
12202386
J Mol Biol. 1995 Apr 7;247(4):536-40
7723011
Proc Natl Acad Sci U S A. 1973 Mar;70(3):697-701
4351801
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2269-75
15572780
Science. 2002 Dec 6;298(5600):1912-34
12471243
Biochemistry. 1984 Nov 6;23(23):5512-9
6439241
J Mol Biol. 1997 Nov 14;273(5):1048-60
9367790
Prog Biophys Mol Biol. 1999;71(2):155-241
10097615
Trends Biochem Sci. 1998 Sep;23(9):358-61
9787643
Curr Opin Chem Biol. 2004 Feb;8(1):14-9
15036151
Methods Enzymol. 2003;374:544-84
14696388
J Mol Biol. 1991 Jul 5;220(1):133-49
2067013
Acta Crystallogr D Biol Crystallogr. 2009 Nov;65(Pt 11):1140-61
19923711
Proteins. 2007 Feb 1;66(2):321-41
17096417
J Mol Biol. 1984 Mar 25;174(1):175-91
6371249
Proteins. 1994 Jul;19(3):183-98
7937733
J Mol Biol. 1982 Jun 15;158(1):111-52
7120407
Structure. 2008 Feb;16(2):321-30
18275822
Prog Biophys Mol Biol. 1993;60(2):73-200
8362069
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Biochemistry. 1994 Jun 7;33(22):6739-49
8204609
Adv Protein Chem. 1979;33:167-241
44431
Nucleic Acids Res. 2000 Apr 15;28(8):1665-75
10734184
Biochemistry. 1970 Jun 23;9(13):2666-77
5465355
Biophys J. 1980 Oct;32(1):139-53
7248446
Biochemistry. 1981 Nov 10;20(23):6544-52
7306523
Nucleic Acids Res. 2003 Jan 1;31(1):478-82
12520056
J Mol Biol. 1981 Jan 5;145(1):215-50
7265198
Structure. 1996 Feb 15;4(2):147-56
8805521
Nucleic Acids Res. 1998 Sep 15;26(18):4280-90
9722650
J Mol Biol. 2004 Jun 4;339(3):647-78
15147847
Science. 1988 Dec 16;242(4885):1541-4
3201242
Biochemistry. 1991 Apr 2;30(13):3147-61
2009257
Nature. 1988 Sep 8;335(6186):188-90
3412476
Nature. 1981 May 7;291(5810):85-7
7231527
J Mol Graph Model. 2002 Oct;21(2):151-60
12398345
Nature. 1983 Apr 7;302(5908):500-5
6339948
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W590-4
15215457
Protein Eng. 1989 Oct;3(1):1-3
2813338
Structure. 1997 Aug 15;5(8):1093-108
9309224