title: Orientation-dependent backbone-only residue pair scoring functions for fixed backbone protein design.
abstract: BACKGROUND
  Empirical scoring functions have proven useful in protein structure modeling. Most such scoring functions depend on protein side chain conformations. However, backbone-only scoring functions do not require computationally intensive structure optimization and so are well suited to protein design, which requires fast score evaluation. Furthermore, scoring functions that account for the distinctive relative position and orientation preferences of residue pairs are expected to be more accurate than those that depend only on the separation distance.
  
  
  RESULTS
  Residue pair scoring functions for fixed backbone protein design were derived using only backbone geometry. Unlike previous studies that used spherical harmonics to fit 2D angular distributions, Gaussian Mixture Models were used to fit the full 3D (position only) and 6D (position and orientation) distributions of residue pairs. The performance of the 1D (residue separation only), 3D, and 6D scoring functions were compared by their ability to identify correct threading solutions for a non-redundant benchmark set of protein backbone structures. The threading accuracy was found to steadily increase with increasing dimension, with the 6D scoring function achieving the highest accuracy. Furthermore, the 3D and 6D scoring functions were shown to outperform side chain-dependent empirical potentials from three other studies. Next, two computational methods that take advantage of the speed and pairwise form of these new backbone-only scoring functions were investigated. The first is a procedure that exploits available sequence data by averaging scores over threading solutions for homologs. This was evaluated by applying it to the challenging problem of identifying interacting transmembrane alpha-helices and found to further improve prediction accuracy. The second is a protein design method for determining the optimal sequence for a backbone structure by applying Belief Propagation optimization using the 6D scoring functions. The sensitivity of this method to backbone structure perturbations was compared with that of fixed-backbone all-atom modeling by determining the similarities between optimal sequences for two different backbone structures within the same protein family. The results showed that the design method using 6D scoring functions was more robust to small variations in backbone structure than the all-atom design method.
  
  
  CONCLUSIONS
  Backbone-only residue pair scoring functions that account for all six relative degrees of freedom are the most accurate and including the scores of homologs further improves the accuracy in threading applications. The 6D scoring function outperformed several side chain-dependent potentials while avoiding time-consuming and error prone side chain structure prediction. These scoring functions are particularly useful as an initial filter in protein design problems before applying all-atom modeling.
authors.affiliation: Mayo Clinic, Scottsdale, AZ 85259, USA. bordner.andrew@mayo.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bordner
mesh_terms: D019295:Computational Biology; D030562:Databases, Protein; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins
references.citation: Bioinformatics. 2006 Jul 1;22(13):1658-9
references.pmid: 16731699
references.citation: J Mol Biol. 1996 Mar 29;257(2):457-69
references.pmid: 8609636
references.citation: Proteins. 2006 Nov 15;65(3):726-41
references.pmid: 16981202
references.citation: Curr Opin Biotechnol. 1994 Aug;5(4):396-402
references.pmid: 7765172
references.citation: J Mol Graph Model. 2004 May;22(5):441-50
references.pmid: 15099839
references.citation: Proteins. 1994 Nov;20(3):216-26
references.pmid: 7892171
references.citation: J Mol Biol. 1996 Dec 20;264(5):1164-79
references.pmid: 9000638
references.citation: EMBO J. 1986 Apr;5(4):823-6
references.pmid: 3709526
references.citation: Protein Sci. 1998 Nov;7(11):2469-71
references.pmid: 9828015
references.citation: J Mol Biol. 2007 Feb 16;366(2):436-48
references.pmid: 17174324
references.citation: Bioinformatics. 2004 Nov 22;20(17):2964-72
references.pmid: 15180935
references.citation: Proteins. 2008 Feb 15;70(3):950-70
references.pmid: 17847088
references.citation: Science. 1990 Mar 16;247(4948):1306-10
references.pmid: 2315699
references.citation: Proteins. 2007;69 Suppl 8:38-56
references.pmid: 17894352
references.citation: J Mol Biol. 1996 Mar 1;256(3):623-44
references.pmid: 8604144
references.citation: PLoS Comput Biol. 2006 Feb;2(2):e9
references.pmid: 16462939
references.citation: Protein Sci. 2007 Oct;16(10):2123-39
references.pmid: 17893359
references.citation: Protein Sci. 1994 Mar;3(3):522-4
references.pmid: 8019422
references.citation: J Mol Biol. 1998 Feb 6;275(5):895-916
references.pmid: 9480776
references.citation: J Chem Phys. 2005 Jan 8;122(2):024901
references.pmid: 15638624
references.citation: Protein Eng. 1999 Feb;12(2):85-94
references.pmid: 10195279
references.citation: Protein Sci. 2004 Apr;13(4):862-74
references.pmid: 15044723
references.citation: J Mol Biol. 1990 Jun 20;213(4):859-83
references.pmid: 2359125
references.citation: Proteins. 1999 Jan 1;34(1):49-68
references.pmid: 10336383
references.citation: Proteins. 1991;9(1):56-68
references.pmid: 2017436
references.citation: J Mol Biol. 1994 Feb 4;235(5):1598-613
references.pmid: 8107094
references.citation: J Mol Biol. 1997 Oct 17;273(1):355-68
references.pmid: 9367768
references.citation: Fold Des. 1997;2(3):S19-24
references.pmid: 9218962
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: Proteins. 2004 May 15;55(3):656-77
references.pmid: 15103629
references.citation: Proteins. 2000 Oct 1;41(1):40-6
references.pmid: 10944392
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10383-8
references.pmid: 10984534
references.citation: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D275-8
references.pmid: 15608195
references.citation: Curr Opin Struct Biol. 1996 Jun;6(3):377-85
references.pmid: 8804824
references.citation: J Mol Biol. 2008 Feb 8;376(1):288-301
references.pmid: 18177896
references.citation: Fold Des. 1996;1(5):357-70
references.pmid: 9080182
references.citation: Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
references.pmid: 15034147