title: A search for energy minimized sequences of proteins.
abstract: In this paper, we present numerical evidence that supports the notion of minimization in the sequence space of proteins for a target conformation. We use the conformations of the real proteins in the Protein Data Bank (PDB) and present computationally efficient methods to identify the sequences with minimum energy. We use edge-weighted connectivity graph for ranking the residue sites with reduced amino acid alphabet and then use continuous optimization to obtain the energy-minimizing sequences. Our methods enable the computation of a lower bound as well as a tight upper bound for the energy of a given conformation. We validate our results by using three different inter-residue energy matrices for five proteins from protein data bank (PDB), and by comparing our energy-minimizing sequences with 80 million diverse sequences that are generated based on different considerations in each case. When we submitted some of our chosen energy-minimizing sequences to Basic Local Alignment Search Tool (BLAST), we obtained some sequences from non-redundant protein sequence database that are similar to ours with an E-value of the order of 10(-7). In summary, we conclude that proteins show a trend towards minimizing energy in the sequence space but do not seem to adopt the global energy-minimizing sequence. The reason for this could be either that the existing energy matrices are not able to accurately represent the inter-residue interactions in the context of the protein environment or that Nature does not push the optimization in the sequence space, once it is able to perform the function.
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
authors.forename: Anupam Nath
authors.initials: AN
authors.lastname: Jha
authors.forename: G K
authors.initials: GK
authors.lastname: Ananthasuresh
authors.forename: Saraswathi
authors.initials: S
authors.lastname: Vishveshwara
mesh_terms: D000595:Amino Acid Sequence; D030562:Databases, Protein; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins
references.citation: Protein Sci. 1995 Oct;4(10):2006-18
references.pmid: 8535237
references.citation: Structure. 1999 May;7(5):R105-9
references.pmid: 10378265
references.citation: J Mol Biol. 2002 Jan 18;315(3):471-7
references.pmid: 11786026
references.citation: Biophys J. 2005 Dec;89(6):4159-70
references.pmid: 16150969
references.citation: J Mol Biol. 2001 Mar 16;307(1):429-45
references.pmid: 11243829
references.citation: Curr Opin Struct Biol. 2002 Aug;12(4):453-8
references.pmid: 12163067
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: J Mol Biol. 2001 Feb 23;306(3):607-28
references.pmid: 11178917
references.citation: J Theor Biol. 2007 Sep 7;248(1):81-90
references.pmid: 17543996
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5803-7
references.pmid: 8016069
references.citation: J Struct Biol. 2001 May-Jun;134(2-3):269-81
references.pmid: 11551185
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5869-74
references.pmid: 16581913
references.citation: J Mol Biol. 1994 Jun 3;239(2):249-75
references.pmid: 8196057
references.citation: Science. 1997 Oct 3;278(5335):82-7
references.pmid: 9311930
references.citation: Protein Sci. 1998 Sep;7(9):1939-46
references.pmid: 9761474
references.citation: J Mol Biol. 1997 Nov 7;273(4):789-96
references.pmid: 9367772
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):691-6
references.pmid: 11782533
references.citation: J Mol Biol. 1996 Mar 1;256(3):623-44
references.pmid: 8604144
references.citation: Nature. 1992 Apr 9;356(6369):539-42
references.pmid: 21488406
references.citation: J Biosci. 2007 Aug;32(5):883-9
references.pmid: 17914230
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1280-5
references.pmid: 11805293
references.citation: J Mol Biol. 2003 Jul 18;330(4):813-9
references.pmid: 12850149
references.citation: Science. 1973 Jul 20;181(4096):223-30
references.pmid: 4124164
references.citation: Annu Rev Biophys Biomol Struct. 2006;35:49-65
references.pmid: 16689627
references.citation: J Theor Biol. 2008 Jan 21;250(2):291-7
references.pmid: 17981305
references.citation: Proc Natl Acad Sci U S A. 1992 May 1;89(9):4163-7
references.pmid: 1570343
references.citation: J Mol Biol. 2003 Sep 12;332(2):449-60
references.pmid: 12948494
references.citation: J Mol Biol. 1999 Nov 12;293(5):1161-81
references.pmid: 10547293
references.citation: J Mol Biol. 1994 Feb 25;236(3):918-39
references.pmid: 8114102
references.citation: Biophys J. 2008 Jan 15;94(2):584-99
references.pmid: 17827237
references.citation: J Am Chem Soc. 2003 Jul 16;125(28):8422-3
references.pmid: 12848533
references.citation: Chem Rev. 2001 Oct;101(10):3113-30
references.pmid: 11710064
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10383-8
references.pmid: 10984534
references.citation: J Mol Biol. 1999 Nov 12;293(5):1183-93
references.pmid: 10547294
references.citation: J Mol Biol. 1994 Nov 4;243(4):668-82
references.pmid: 7966290
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712