title: On the satisfaction of backbone-carbonyl lone pairs of electrons in protein structures.
abstract: Protein structures are stabilized by a variety of noncovalent interactions (NCIs), including the hydrophobic effect, hydrogen bonds, electrostatic forces and van der Waals' interactions. Our knowledge of the contributions of NCIs, and the interplay between them remains incomplete. This has implications for computational modeling of NCIs, and our ability to understand and predict protein structure, stability, and function. One consideration is the satisfaction of the full potential for NCIs made by backbone atoms. Most commonly, backbone-carbonyl oxygen atoms located within α-helices and β-sheets are depicted as making a single hydrogen bond. However, there are two lone pairs of electrons to be satisfied for each of these atoms. To explore this, we used operational geometric definitions to generate an inventory of NCIs for backbone-carbonyl oxygen atoms from a set of high-resolution protein structures and associated molecular-dynamics simulations in water. We included more-recently appreciated, but weaker NCIs in our analysis, such as n→π* interactions, Cα-H bonds and methyl-H bonds. The data demonstrate balanced, dynamic systems for all proteins, with most backbone-carbonyl oxygen atoms being satisfied by two NCIs most of the time. Combinations of NCIs made may correlate with secondary structure type, though in subtly different ways from traditional models of α- and β-structure. In addition, we find examples of under- and over-satisfied carbonyl-oxygen atoms, and we identify both sequence-dependent and sequence-independent secondary-structural motifs in which these reside. Our analysis provides a more-detailed understanding of these contributors to protein structure and stability, which will be of use in protein modeling, engineering and design.
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, United Kingdom.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Bartlett
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, United Kingdom.|School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.|BrisSynBio, a BBSRC/EPSRC-Funded Synthetic Biology Research Centre, Life Sciences Building, Bristol, BS8 1TQ, United Kingdom.
authors.forename: Derek N
authors.initials: DN
authors.lastname: Woolfson
mesh_terms: D003198:Computer Simulation; D004583:Electrons; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D014867:Water / Q000737:chemistry*
chemical_list: D011506:Proteins; D014867:Water
keywords: bioinformatics; hydrogen bonding; noncovalent interactions; n→π* interactions; protein folding; protein stability; protein structure
references.citation: J Chem Theory Comput. 2013;9(9):4046-4063
references.pmid: 24163642
references.citation: Proteins. 2010 Jun;78(8):1950-8
references.pmid: 20408171
references.citation: J Am Chem Soc. 2013 Dec 11;135(49):18682-8
references.pmid: 24256417
references.citation: J Am Chem Soc. 2004 Sep 22;126(37):11675-83
references.pmid: 15366915
references.citation: Protein Sci. 1998 Jan;7(1):21-38
references.pmid: 9514257
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Bioinformatics. 2013 Apr 1;29(7):845-54
references.pmid: 23407358
references.citation: Proteins. 2014 Nov;82(11):3023-31
references.pmid: 25132631
references.citation: Protein Sci. 2011 Feb;20(2):417-27
references.pmid: 21280132
references.citation: Proteins. 2015 Mar;83(3):403-10
references.pmid: 25401519
references.citation: J Mol Biol. 2001 Jan 19;305(3):535-57
references.pmid: 11152611
references.citation: J Mol Biol. 1994 May 20;238(5):777-93
references.pmid: 8182748
references.citation: Proteins. 2012 Apr;80(4):991-1002
references.pmid: 22228445
references.citation: Nat Chem. 2010 Jun;2(6):466-71
references.pmid: 20489715
references.citation: Science. 1988 Jun 17;240(4859):1648-52
references.pmid: 3381086
references.citation: Biopolymers. 1983 Dec;22(12):2577-637
references.pmid: 6667333
references.citation: J Mol Biol. 2001 Mar 16;307(1):357-77
references.pmid: 11243825
references.citation: Angew Chem Int Ed Engl. 2002 Jan 4;41(1):49-76
references.pmid: 12491444
references.citation: J Chem Phys. 2007 Jan 7;126(1):014101
references.pmid: 17212484
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16623-33
references.pmid: 17075053
references.citation: Protein Sci. 1996 Feb;5(2):212-20
references.pmid: 8745398
references.citation: Protein Sci. 2011 Jun;20(6):1077-81
references.pmid: 21442680
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: Protein Sci. 2005 Nov;14(11):2910-4
references.pmid: 16251367
references.citation: Science. 1973 Jul 20;181(4096):223-30
references.pmid: 4124164
references.citation: Biochemistry. 1990 Aug 7;29(31):7133-55
references.pmid: 2207096
references.citation: Angew Chem Int Ed Engl. 2011 Jan 3;50(1):52-9
references.pmid: 21031379
references.citation: PLoS One. 2015 Apr 20;10(4):e0123146
references.pmid: 25894612
references.citation: Org Lett. 2006 Oct 12;8(21):4695-7
references.pmid: 17020280
references.citation: J Mol Graph Model. 2008 Aug;27(1):20-33
references.pmid: 18343699
references.citation: J Chem Theory Comput. 2015 Feb 10;11(2):609-22
references.pmid: 25866491
references.citation: Proc Natl Acad Sci U S A. 1936 Jul;22(7):439-47
references.pmid: 16577722
references.citation: Protein Sci. 2005 Jul;14(7):1911-7
references.pmid: 15937286
references.citation: J Am Chem Soc. 2008 Nov 12;130(45):14918-9
references.pmid: 18937471
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10786-91
references.pmid: 10984522
references.citation: FEBS Lett. 2014 Jun 27;588(14):2177-84
references.pmid: 24846139
references.citation: J Am Chem Soc. 2003 Dec 24;125(51):15750-1
references.pmid: 14677958
references.citation: Nature. 1967 Apr 22;214(5086):363-5
references.pmid: 6040611
references.citation: J Biol Chem. 2012 Dec 7;287(50):41576-82
references.pmid: 23048026
references.citation: Protein Sci. 2014 Mar;23(3):284-8
references.pmid: 24375625
references.citation: J Chem Theory Comput. 2014 Nov 11;10(11):5113-5124
references.pmid: 25400522
references.citation: Protein Sci. 2003 Jun;12(6):1188-94
references.pmid: 12761389
references.citation: J Chem Theory Comput. 2008 Jan;4(1):116-22
references.pmid: 26619985
references.citation: Nat Chem Biol. 2010 Aug;6(8):615-20
references.pmid: 20622857
references.citation: J Am Chem Soc. 2013 Oct 16;135(41):15536-48
references.pmid: 24093804
references.citation: J Mol Biol. 1995 Sep 15;252(2):248-62
references.pmid: 7674305