π–π Interactions in Structural Stability: Role in RNA Binding Proteins

RNA binding proteins play significant roles in many bio-macromolecular systems. Aromatic amino acid residues are vital for several biological functions. In the present work, the influences of π–π interactions in RNA binding proteins are analyzed. There are a total of 3,396 π-residues in RNA binding proteins out of which 1,547, 1,241, and 608 are phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), respectively. Among these 945, 634, and 356 Phe, Tyr, and Trp residues, respectively, are involved in π–π interactions. The observations indicate that majority of the aromatic residues in RNA binding proteins are involved in π–π interactions. Side chain–side chain π–π interactions are the predominant type of interactions in RNA binding proteins. These π–π interactions stabilize the core regions within RNA binding proteins. π–π interacting residues are evolutionary conserved. Residue-wise analysis indicates that π–π interacting residues have higher long-range contacts and hence they are important in the global conformational stability of these proteins.     

Cation–π Interactions in β-Lactamases: The Role in Structural Stability

β-lactam group of antibiotics is the most widely used therapeutic molecules for treating bacterial infections. The main mode of bacterial resistance to β-lactams is by β-lactamases. In the present study, we report our results on the role of cation–π interactions in β-lactamases and their environmental preferences. The number of interactions formed by arginine is higher than lysine in the cationic group, while tyrosine is comparatively higher than phenylalanine and tryptophan in the π group. Our results indicate that cation–π interactions might play an important role in the global conformational stability of β-lactamases.     

Computational Study of ADD1 Gene Polymorphism Associated with Hypertension

We have determined the non-synonymous single-nucleotide polymorphisms (nsSNPs) of ?? adducin 1 (ADD1) gene and its variations in different populations to understand its role in hypertension. Out of 1,113 SNPs, 9 are found to be non-synonymous, of which 7 showed significant damaging effect and one of them showed SNP variability with large differences among the minor allele frequency observed in various populations. The amino acid change found for rs4961 is from glycine to tryptophan, i.e., from an alkyl amino acid to an aromatic amino acid. This residual change is observed in the coiled region of the protein and is also predicted to be disordered by computational algorithm. Protein disorder plays an important role in structural and functional genomics. Hence, because of the complete change in side chains of the amino acid residues occurring in the coiled and disordered region of the protein, the structure of the protein might be altered and the function might be affected, leading to the risk for hypertension.     

Exploring the role of cation-pi interactions in glycoproteins lipid-binding proteins and RNA-binding proteins

We have analyzed and compared the influence of cation-pi interactions in glycoproteins (GPs), lipid-binding proteins (LBPs) and RNA-binding proteins (RBPs) in this study. We observed that all the proteins included in the study had profound cation-pi interactions. There is an average of one energetically significant cation-pi interaction for every 71 residues in GPs, for every 58 residues in LBPs and for every 64 residues in RBPs. Long-range contacts are predominant in all the three types of proteins studied. The pair-wise cation-pi interaction energy between the positively charged and aromatic residues shows that Arg-Trp pair energy was the strongest among all six possible pairs in all the three types of proteins studied. There were considerable differences in the preference of cation-pi interacting residues to different secondary structure elements and ASA and these might contribute to differences in biochemical functions of GPs, LBPs and RBPs. It was interesting to note that all the five residues involved in cation-pi interactions were found to have stabilization centers in GPs, LBPs and RBPs. Majority of the cation-pi interacting residues investigated in the present study had a conservation score of 6, the cutoff value used to identify the stabilizing residues. A small percentage of cation-pi interacting residues were also present as stabilizing residues. The cation-pi interaction-forming residues play an important role in the structural stability of in GPs, LBPs and RBPs. The results obtained in this study will be helpful in further understanding the stability, specificity and differences in the biochemical functions of GPs, LBPs and RBPs.     

Investigations on unconventional hydrogen bonds in RNA binding proteins: the role of CH...O=C interactions

We have investigated the roles played by C-H...O=C interactions in RNA binding proteins. There was an average of 78 CH...O=C interactions per protein and also there was an average of one significant CH...O=C interactions for every 6 residues in the 59 RNA binding proteins studied. Main chain-Main chain (MM) CH...O=C interactions are the predominant type of interactions in RNA binding proteins. The donor atom contribution to CH...O=C interactions was mainly from aliphatic residues. The acceptor atom contribution for MM CH...O=C interactions was mainly from Val, Phe, Leu, Ile, Arg and Ala. The secondary structure preference analysis of CH...O=C interacting residues showed that, Arg, Gln, Glu and Tyr preferred to be in helix, while Ala, Asp, Cys, Gly, Ile, Leu, Lys, Met, Phe, Trp and Val preferred to be in strand conformation. Most of the CH...O=C interacting polar amino acid residues were solvent exposed while, majority of the CH...O=C interacting non polar residues were excluded from the solvent. Long and medium-range CH...O=C interactions are the predominant type of interactions in RNA binding proteins. More than 50% of CH...O=C interacting residues had a higher conservation score. Significant percentage of CH...O=C interacting residues had one or more stabilization centers. Sixty-six percent of the theoretically predicted stabilizing residues were also involved in CH...O=C interactions and hence these residues may also contribute additional stability to RNA binding proteins.     

Computation of non-covalent interactions in TNF proteins and interleukins

The roles played by the non-covalent interactions have been investigated for a set of six TNF proteins and nine Interleukins. The stabilizing residues have been identified by a consensus approach using the concepts of available surface area, medium and long-range interactions and conservation of amino acid residues. The cation-pi interactions have been computed based on a geometric approach such as distance and energy criteria. We identified an average of 1 energetically significant cation-pi interactions in every 94 residues in TNF proteins and 1 in every 62 residues in Interleukins. In TNF proteins, the cationic groups Lys preferred to be in helix while Arg preferred to be in strand regions while in Interleukins the Arg residues preferred to be in helix and Lys preferred to be in strand regions. From the available surface area calculations, we found that, almost all the cation and pi residues in TNF proteins and Interleukins were either in buried or partially buried regions and none of them in the exposed regions. Medium and long-range interactions were predominant in both TNF proteins and Interleukins. It was observed that the percentage of stabilizing centers were more in TNF proteins as compared to the Interleukins, while the percentage of conserved residues were more in Interleukins than in TNF proteins. In the stabilizing residues Lys was observed to be a stabilizing residue in both TNF proteins and Interleukins. Among the aromatic group, Phe was seen to be a stabilizing residue in both TNF and Interleukins. We suggest that this study on the computation of cation-pi interactions in TNF proteins and Interleukins would be very helpful in further understanding the structure, stability and functional similarity of these proteins.     

Aromatic-aromatic interactions: analysis of π-π interactions in interleukins and TNF proteins

Aromatic-aromatic hydrogen bonds are important in many areas of chemistry, biology and materials science. In this study we have analyzed the roles played by the π-π interactions in interleukins (ILs) and tumor necrosis factor (TNF) proteins. Majority of π-π interacting residues are conserved in ILs and TNF proteins. The accessible surface area calculations in these proteins reveal that these interactions might be important in stabilizing the inner core regions of these proteins. In addition to π-π interactions, the aromatic residues also form π-networks in ILs and TNF proteins. The results obtained in the present study indicate that π-π interactions and π-π networks play important roles in the structural stability of ILs and TNF proteins.