Cation-π interactions in high resolution protein-RNA complex crystal structures

In this work, we have analyzed the influence of cation-π interactions to the stability of 59 high resolution protein-RNA complex crystal structures. The total number of Lys and Arg are similar in the dataset as well as the number of their interactions. On the other hand, the aromatic chains of purines are exhibiting more cation-π interactions than pyrimidines. 35% of the total interactions in the dataset are involved in the formation of multiple cation-π interactions. The multiple cation-π interactions have been conserved more than the single interactions. The analysis of the geometry of the cation-π interactions has revealed that the average distance (d) value falls into distinct ranges corresponding to the multiple (4.28 Å) and single (5.50 Å) cation-π interactions. The G-Arg pair has the strongest interaction energy of -3.68 kcal mol(-1) among all the possible pairs of amino acids and bases. Further, we found that the cation-π interactions due to five-membered rings of A and G are stronger than that with the atoms in six-membered rings. 8.7% stabilizing residues are involved in building cation-π interactions with the nucleic bases. There are three types of structural motifs significantly over-represented in protein-RNA interfaces: beta-turn-ir, niche-4r and st-staple. Tetraloops and kink-turns are the most abundant RNA motifs in protein-RNA interfaces. Amino acids deployed in the protein-RNA interfaces are deposited in helices, sheets and coils. Arg and Lys, involved in cation-π interactions, prefer to be in the solvent exposed surface. The results from this study might be used for structure-based prediction and as scaffolds for future protein-RNA complex design.

[1]  J. Watson,et al.  A novel main-chain anion-binding site in proteins: the nest. A particular combination of phi,psi values in successive residues gives rise to anion-binding sites that occur commonly and are found often at functionally important regions. , 2002, Journal of molecular biology.

[2]  Adel Golovin,et al.  MSDmotif: exploring protein sites and motifs , 2008, BMC Bioinformatics.

[3]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[4]  K. Ramanathan,et al.  A compact review on the comparison of conventional and non-conventional interactions on the structural stability of therapeutic proteins , 2011, Interdisciplinary Sciences: Computational Life Sciences.

[5]  A. Fiser,et al.  Stabilization centers in proteins: identification, characterization and predictions. , 1997, Journal of molecular biology.

[6]  M. Michael Gromiha,et al.  Influence of cation–π interactions in protein–DNA complexes , 2004 .

[7]  K. Hall,et al.  RNA-protein interactions. , 2002, Current opinion in structural biology.

[8]  Maria Jesus Martin,et al.  The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003 , 2003, Nucleic Acids Res..

[9]  Lili Wan,et al.  RNA and Disease , 2009, Cell.

[10]  Zsuzsanna Dosztányi,et al.  SCide: Identification of Stabilization Centers in Proteins , 2003, Bioinform..

[11]  Y. Shamoo,et al.  Structure-based analysis of protein-RNA interactions using the program ENTANGLE. , 2001, Journal of molecular biology.

[12]  R. Sethumadhavan,et al.  NH - π Interactions: Investigations on the Evidence and Consequences in RNA Binding Proteins , 2008 .

[13]  Michael B. Hall,et al.  A reexamination of the propensities of amino acids towards a particular secondary structure: classification of amino acids based on their chemical structure , 2008, Journal of molecular modeling.

[14]  Pamela L. Vanegas,et al.  RNA CoSSMos: Characterization of Secondary Structure Motifs—a searchable database of secondary structure motifs in RNA three-dimensional structures , 2011, Nucleic Acids Res..

[15]  Vasant Honavar,et al.  PRIDB: a protein–RNA interface database , 2010, Nucleic Acids Res..

[16]  Dong Young Kim,et al.  Comprehensive Energy Analysis for Various Types of π-Interaction. , 2009, Journal of chemical theory and computation.

[17]  M. Gribskov,et al.  The role of RNA sequence and structure in RNA--protein interactions. , 2011, Journal of molecular biology.

[18]  V. Prasad,et al.  Influence of cation–π interactions to the structural stability of prokaryotic and eukaryotic translation elongation factors , 2009, Protoplasma.

[19]  D. Craik,et al.  The cystine knot motif in toxins and implications for drug design. , 2001, Toxicon : official journal of the International Society on Toxinology.

[20]  D A Dougherty,et al.  A mechanism for ion selectivity in potassium channels: computational studies of cation-pi interactions. , 1993, Science.

[21]  Harianto Tjong,et al.  DISPLAR: an accurate method for predicting DNA-binding sites on protein surfaces , 2007, Nucleic acids research.

[22]  Alfonso Mondragón,et al.  Emerging structural themes in large RNA molecules. , 2011, Current opinion in structural biology.

[23]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[24]  Sudha Ramaiah,et al.  Cation–π Interactions in β-Lactamases: The Role in Structural Stability , 2013, Cell Biochemistry and Biophysics.

[25]  Raju S. Bapi,et al.  Protein ligand interaction database (PLID) , 2008, Comput. Biol. Chem..

[26]  Kyungsook Han,et al.  Computational analysis of hydrogen bonds in protein–RNA complexes for interaction patterns , 2003, FEBS letters.

[27]  M. Babu,et al.  Investigations on C-H...pi interactions in RNA binding proteins. , 2007, International journal of biological macromolecules.

[28]  Kangnian Fan,et al.  A theoretical study on the metal cation-π complexes of Zn2+ and Cd2+ with benzene and cyclohexene , 2009 .

[29]  Alberto Apostolico,et al.  Finding 3D motifs in ribosomal RNA structures , 2009, Nucleic acids research.

[30]  Dolly Vijay,et al.  Exploring the size dependence of cyclic and acyclic pi-systems on cation-pi binding. , 2008, Physical chemistry chemical physics : PCCP.

[31]  M Michael Gromiha,et al.  ROLE OF CATION-π INTERACTIONS TO THE STABILITY OF THERMOPHILIC PROTEINS , 2002, Preparative biochemistry & biotechnology.

[32]  M. Michael Gromiha,et al.  Exploring the environmental preference of weak interactions in (α/β)8 barrel proteins , 2006 .

[33]  D. A. Dougherty,et al.  Cation-π interactions in structural biology , 1999 .

[34]  W. Delano.  Unraveling hot spots in binding interfaces: progress and challenges. , 2002, Current opinion in structural biology.

[35]  E Westhof,et al.  Statistical analysis of atomic contacts at RNA–protein interfaces , 2001, Journal of molecular recognition : JMR.

[36]  Jonathan J. Ellis,et al.  Protein–RNA interactions: Structural analysis and functional classes , 2006, Proteins.

[37]  G. Madhavi Sastry,et al.  From subtle to substantial : Role of metal ions on π-π interactions , 2006 .

[38]  M. Gromiha.  Influence of cation-pi interactions in different folding types of membrane proteins. , 2003, Biophysical chemistry.

[39]  F. Diederich,et al.  Aromatic rings in chemical and biological recognition: energetics and structures. , 2011, Angewandte Chemie.

[40]  Guoli Wang,et al.  PISCES: recent improvements to a PDB sequence culling server , 2005, Nucleic Acids Res..

[41]  N. Morozova,et al.  Protein-RNA interactions: exploring binding patterns with a three-dimensional superposition analysis of high resolution structures , 2006, Bioinform..

[42]  S. Stojanović,et al.  Non-canonical interactions of porphyrins in porphyrin-containing proteins , 2012, Amino Acids.

[43]  U. D. Priyakumar,et al.  A computational study of cation–π interactions in polycyclic systems: exploring the dependence on the curvature and electronic factors ☆ , 2004 .

[44]  Peng Zhou,et al.  Geometric similarity between protein–RNA interfaces , 2009, J. Comput. Chem..

[45]  Kai-Wei Chang,et al.  RNA-binding proteins in human genetic disease. , 2008, Trends in genetics : TIG.

[46]  Hendrik Zipse,et al.  On the cooperativity of cation-pi and hydrogen bonding interactions. , 2008, The journal of physical chemistry. B.

[47]  M. Rodgers,et al.  Influence of substituents on cation-π interactions , 2003 .

[48]  S. Stojanović,et al.  π–π and cation–π interactions in protein–porphyrin complex crystal structures , 2012 .

[49]  D. A. Dougherty,et al.  The Cationminus signpi Interaction. , 1997, Chemical reviews.

[50]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[51]  T. Glisovic,et al.  RNA‐binding proteins and post‐transcriptional gene regulation , 2008, FEBS letters.

[52]  M. Michael Gromiha,et al.  SRide: a server for identifying stabilizing residues in proteins , 2005, Nucleic Acids Res..

[53]  J. Iwakiri,et al.  Dissecting the protein–RNA interface: the role of protein surface shapes and RNA secondary structures in protein–RNA recognition , 2011, Nucleic acids research.

[54]  M. Rodgers,et al.  Sigma versus Pi Interactions in Alkali Metal Ion Binding to Azoles: Threshold Collision-Induced Dissociation and ab Initio Theory Studies , 2002 .

[55]  S. Karlin,et al.  Geometry of interplanar residue contacts in protein structures. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Thomas Tuschl,et al.  Functional genomics: RNA sets the standard , 2003, Nature.

[57]  G. N. Sastry,et al.  Cation-π interaction: its role and relevance in chemistry, biology, and material science. , 2013, Chemical reviews.

[58]  Jessica L. Childs-Disney,et al.  Controlling the specificity of modularly assembled small molecules for RNA via ligand module spacing: targeting the RNAs that cause myotonic muscular dystrophy. , 2009, Journal of the American Chemical Society.

[59]  B. Herbert,et al.  Characterization of Cation–π Interactions in Aqueous Solution Using Deuterium Nuclear Magnetic Resonance Spectroscopy , 2004 .

[60]  R. Sethumadhavan,et al.  Exploring the role of cation-pi interactions in glycoproteins lipid-binding proteins and RNA-binding proteins. , 2007, Journal of theoretical biology.

[61]  Anand Anbarasu,et al.  Investigations on unconventional hydrogen bonds in RNA binding proteins: The role of CH..O=C interactions , 2007, Biosyst..

[62]  A. Sarai,et al.  Analysis of electric moments of RNA-binding proteins: implications for mechanism and prediction , 2011, BMC Structural Biology.