Protein structure and evolutionary history determine sequence space topology.
Understanding the observed variability in the number of homologs of a gene is a very important unsolved problem that has broad implications for research into coevolution of structure and function, gene duplication, pseudogene formation, and possibly for emerging diseases. Here, we attempt to define and elucidate some possible causes behind the observed irregularity in sequence space. We present evidence that sequence variability and functional diversity of a gene or fold family is influenced by quantifiable characteristics of the protein structure. These characteristics reflect the structural potential for sequence plasticity, i.e., the ability to accept mutation without losing thermodynamic stability. We identify a structural feature of a protein domain-contact density-that serves as a determinant of entropy in sequence space, i.e., the ability of a protein to accept mutations without destroying the fold (also known as fold designability). We show that (log) of average gene family size exhibits statistical correlation (R(2) > 0.9.) with contact density of its three-dimensional structure. We present evidence that the size of individual gene families are influenced not only by the designability of the structure, but also by evolutionary history, e.g., the amount of time the gene family was in existence. We further show that our observed statistical correlation between gene family size and contact density of the structure is valid on many levels of evolutionary divergence, i.e., not only for closely related sequence, but also for less-related fold and superfamily levels of homology.
Shakhnovich
Boris E
BE
Bioinformatics Program, Boston University, Boston, Massachusetts 02215, USA.
Deeds
Eric
E
Delisi
Charles
C
Shakhnovich
Eugene
E
D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D011506:Proteins
Phys Rev Lett. 2000 Sep 18;85(12):2641-4
10978127
J Mol Biol. 1987 Jul 5;196(1):199-216
3656444
Bioinformatics. 2000 Dec;16(12):1145-50
11159333
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14132-6
12384571
Bioinformatics. 1998 Jun;14(5):423-9
9682055
Subcell Biochem. 1995;24:1-26
7900172
Nucleic Acids Res. 2003 Jan 1;31(1):489-91
12520059
Fold Des. 1998;3(3):R45-58
9669878
Trends Biochem Sci. 2002 Oct;27(10):514-20
12368087
Acc Chem Res. 2002 May;35(5):261-9
12020163
Nucleic Acids Res. 2001 Jan 1;29(1):55-7
11125048
Genome Res. 2001 Oct;11(10):1632-40
11591640
Biophys J. 2003 Nov;85(5):2962-72
14581198
Science. 1996 Aug 2;273(5275):666-9
8662562
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3341-5
8622938
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8727-31
12843403
Curr Opin Struct Biol. 1999 Jun;9(3):374-82
10361094
Proteins. 2002 Jun 1;47(4):506-12
12001229
Genome Res. 2002 Jul;12(7):1048-59
12097341
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14249-55
8962034
Curr Opin Struct Biol. 1999 Jun;9(3):390-9
10361097
Nature. 2002 Nov 14;420(6912):218-23
12432406
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1280-5
11805293
Nat Genet. 2000 May;25(1):25-9
10802651
Mol Biol Evol. 1998 May;15(5):583-9
9580988
Methods Biochem Anal. 2003;44:249-71
12647390
Nucleic Acids Res. 2003 Jan 1;31(1):365-70
12520024
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2846-51
14970345
Science. 2001 Oct 5;294(5540):93-6
11588250
Biopolymers. 2000 Jan;53(1):1-8
10644946
BMC Evol Biol. 2003 Jan 6;3:2
12515582
Nat Struct Biol. 2001 Jun;8(6):559-66
11373627
Nucleic Acids Res. 1998 Jan 1;26(1):320-2
9399864
Prog Biophys Mol Biol. 1987;50(3):171-90
3332386
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Annu Rev Biophys Biomol Struct. 2002;31:45-71
11988462
J Mol Biol. 1993 Sep 5;233(1):123-38
8377180
Phys Rev Lett. 2003 May 30;90(21):218101
12786593
J Mol Biol. 2001 Nov 2;313(4):673-81
11697896