Conformational Studies of Polyprolines

Proline rich peptide sequences are very important recognition elements that have a significant bias toward the all-trans-polyproline type II (PII) conformation. Our gas-phase quantum mechanics calculations at the B3LYP/6-31G* level of theory are in good agreement with previous experimental and theoretical studies. They show that all-trans-proline conformations are energetically more favorable than all-cis-polyprolines (PI, polyproline type I). Estimates of the solvent effects show that the condensed phase can make the PI form more populated in the correct environment. Our survey of proline oligomers in the Protein Data Bank confirmed that the predominant conformations from our calculations are seen experimentally. More importantly, we propose two new secondary structures for polyprolines, namely polyproline type III and type IV (PIII and PIV). PIII is a right-handed, “square helix” from trans-proline oligomers. PIV is a β-sheet form of cis-prolines. As suggested by its calculated IR spectra, the PIII form shares characteristics of both the PI and PII forms:  it has trans-amide rotamers similar to PII and forms a right-handed helix like PI. We propose that the high-energy PIII form could exist as a conformational intermediate between PI and PII. These new forms also show that the handedness of polyproline helices depends not only on the peptide rotamers (cis or trans) but also on the values of the ψ torsions. Changing the ψ torsion from approximately 140° to approximately −30° causes the trans oligomers to flip from a typical left-handed PII to a right-handed helix. Likewise, as the ψ torsion of the cis-proline oligomers changes from roughly 165° to −30°, the conformation changes from a characteristic right-handed PI to a β-sheet

Conformational Studies of Polyprolines

Proline rich peptide sequences are very important recognition elements that have a significant bias toward the all-trans-polyproline type II (PII) conformation. Our gas-phase quantum mechanics calculations at the B3LYP/6-31G* level of theory are in good agreement with previous experimental and theoretical studies. They show that all-trans-proline conformations are energetically more favorable than all-cis-polyprolines (PI, polyproline type I). Estimates of the solvent effects show that the condensed phase can make the PI form more populated in the correct environment. Our survey of proline oligomers in the Protein Data Bank confirmed that the predominant conformations from our calculations are seen experimentally. More importantly, we propose two new secondary structures for polyprolines, namely polyproline type III and type IV (PIII and PIV). PIII is a right-handed, “square helix” from trans-proline oligomers. PIV is a β-sheet form of cis-prolines. As suggested by its calculated IR spectra, the PIII form shares characteristics of both the PI and PII forms:  it has trans-amide rotamers similar to PII and forms a right-handed helix like PI. We propose that the high-energy PIII form could exist as a conformational intermediate between PI and PII. These new forms also show that the handedness of polyproline helices depends not only on the peptide rotamers (cis or trans) but also on the values of the ψ torsions. Changing the ψ torsion from approximately 140° to approximately −30° causes the trans oligomers to flip from a typical left-handed PII to a right-handed helix. Likewise, as the ψ torsion of the cis-proline oligomers changes from roughly 165° to −30°, the conformation changes from a characteristic right-handed PI to a β-sheet

Docking Studies on Isoform-Specific Inhibition of Phosphoinositide-3-Kinases

Phosphatidylinositol 3-kinase α (PI3Kα) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3Kα kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3Kα, the H1047R mutant of PI3Kα and the γ isoform of PI3K (PI3Kγ). We also investigated the effect of protein flexibility on ligand binding by docking the same set of ligands to conformations of the wt and mutant PI3Kα generated by molecular dynamics simulations. Our data suggests that conformational differences in Gln859, Ser854, Tyr836, and Ser774 between the PI3Kα wt and H1047R mutant may be used to design ligands that are active against both the wt and H1047R mutant isoforms. Gln859, Ser854 and Ser774 may play critical roles in ligand binding to the α isoform H1047R mutant while formation of H-bonds with Ser806 of PI3Kγ may enhance γ-isoform-specific inhibition. In addition to H-bond interactions, structural and size differences in the activation and hydrophobic domains of PI3Kα, PI3Kγ, and the PI3Kα H1047R mutant could be exploited to direct the design of isoform- and/or mutant-specific PI3K inhibitors. Our data provide a reasonable explanation for the activity and selectivity of small molecular PI3K inhibitors and are in good agreement with available experimental and computational data

Ab Initio and DFT Conformational Studies of Propanal, 2-Butanone, and Analogous Imines and Enamines

The potential energy surfaces (PES) of 2-butanone, 2-butanimine, 1-butenamine, propanal, and propanimine have been explored with ab initio and DFT calculations at the RHF/6-311G**, MP2/6-311G**, and B3LYP/6-311G** levels of theory. In agreement with previous experimental and computational results, the PES provides two minima for each of the above molecules with the exception of 2-butanone, which clearly shows three distinct minima. Factors influencing the conformational preferences are also elaborated. Our calculations suggest that for 2-butanone and propanal, the steric and the bond dipole interactions are primarily responsible for the conformational preferences of these compounds. Additional charge−charge interactions might also play an important role in determining the imine conformations. For enamines, however, steric interactions play a critical role, with bond dipole interactions exerting some influence. Our results also suggest that for imine formation from butanone and/or propanal, the imine is the predominant product, not the enamine, which is consistent with experimental observations. Therefore, these calculations should provide a better understanding of the ketone/aldehyde to imine and enamine transformations. This transformation may introduce an important imine moiety for the analogues of trans-N-methyl-4-(1-naphthylvinyl)pyridine (NVP), a choline acetyltransferase (ChAT) inhibitor

Small Molecule Inhibitors of the MDM2-p53 Interaction Discovered by Ensemble-Based Receptor Models

Five nonpeptide, small-molecule inhibitors of the human MDM2−p53 interaction are presented, and each inhibitor represents a new scaffold. The most potent compound exhibited a Ki of 110 ± 30 nM. These compounds were identified using our multiple protein structure (MPS) method which incorporates protein flexibility into a receptor-based pharmacophore model that identifies appropriate hotspots of binding. Docking the inhibitors with an induced-fit docking protocol suggested that the inhibitors mimicked the three critical binding residues of p53 (Phe19, Trp23, and Leu26). Docking also predicted a new orientation of the scaffolds that more fully fills the binding cleft, enabling the inhibitors to take advantage of additional hydrogen-bonding possibilities not explored by other small molecule inhibitors. One inhibitor in particular was proposed to probe the hydrophobic core of the protein by taking advantage of the flexibility of the binding cleft floor. These results show that the MPS technique is a promising advance for structure-based drug discovery and that the method can truly explore broad chemical space efficiently in the quest to discover potent, small-molecule inhibitors of protein−protein interactions. Our MPS technique is one of very few ensemble-based techniques to be proven through experimental verification of the discovery of new inhibitors

The Impact of Ionization States of Matrix Metalloproteinase Inhibitors on Docking-Based Inhibitor Design

The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model was developed based on the deprotonated compounds and was used to identify four structurally diverse compounds with antiproliferative activities

Maximum-likelihood (ML) tree of influenza A NA subtypes.

<p>A: N1; B: N2; C: N5; D: N8. The annotation for each lineage was labeled on the trees. Three lineages in N1 (1A, 1B and 1C), two lineages in N2 (2A and 2B), two lineages in N5 (5A and 5B), and two lineages in N8 (8A and 8B) were classified. The bootstrap values supporting the corresponding lineages are shown to the left of the major nodes. Scale bars indicate the numbers of nucleotide substitutions per site.</p

Synthesis and Optical Properties of Triphenylene-Based Dendritic Donor Perylene Diimide Acceptor Systems

A donor−acceptor charge transfer system based on two discotic mesogens has been synthesized. The donor is either a triphenylene (POG0) or a triphenylene-based conjugated dendron (POG1), while the acceptor is a perylene diimide (PDI) core. The donors are covalently linked to the bay positions of the PDI core through an ether linkage. In chloroform, due to the short donor−acceptor distance and the matching frontier orbital levels, photoinduced charge transfer from either the donor excitation or the acceptor excitation are both thermodynamically and kinetically favored, resulting in efficient quenching of both donor and acceptor fluorescence. In a less polar solvent, hexane, while charge transfer is still the dominant mechanism for decay of the excited electronic state of POG1, photoinduced charge transfer is no longer energetically favorable for POG0 when the acceptor PDI core is excited, making the PDI core of POG0 weakly fluorescent in chloroform but strongly so in hexane. In solid film, POG0 is highly aggregated through both PDI−PDI and triphenylene−triphenylene homotopic stacking. POG1, on the other hand, aggregates through triphenylene dendrons with limited PDI−PDI core stacking, presumably due to the steric hindrance caused by bulky triphenylene moieties which block the access to the PDI core. The efficient photoinduced charge transfer, coupled with the homotopic stacking that forms separated electron-transporting PDI-stacked columns and hole transporting triphenylene-stacked columns, suggests that the reported donor−acceptor systems based on dual-discotic mesogens are potentially new efficient photovoltaic materials

Evolutionary History and Phylodynamics of Influenza A and B Neuraminidase (NA) Genes Inferred from Large-Scale Sequence Analyses

<div><p>Background</p><p>Influenza neuraminidase (NA) is an important surface glycoprotein and plays a vital role in viral replication and drug development. The NA is found in influenza A and B viruses, with nine subtypes classified in influenza A. The complete knowledge of influenza NA evolutionary history and phylodynamics, although critical for the prevention and control of influenza epidemics and pandemics, remains lacking.</p><p>Methodology/Principal findings</p><p>Evolutionary and phylogenetic analyses of influenza NA sequences using Maximum Likelihood and Bayesian MCMC methods demonstrated that the divergence of influenza viruses into types A and B occurred earlier than the divergence of influenza A NA subtypes. Twenty-three lineages were identified within influenza A, two lineages were classified within influenza B, and most lineages were specific to host, subtype or geographical location. Interestingly, evolutionary rates vary not only among lineages but also among branches within lineages. The estimated tMRCAs of influenza lineages suggest that the viruses of different lineages emerge several months or even years before their initial detection. The <i>d</i>_N<i>/d</i>_S ratios ranged from 0.062 to 0.313 for influenza A lineages, and 0.257 to 0.259 for influenza B lineages. Structural analyses revealed that all positively selected sites are at the surface of the NA protein, with a number of sites found to be important for host antibody and drug binding.</p><p>Conclusions/Significance</p><p>The divergence into influenza type A and B from a putative ancestral NA was followed by the divergence of type A into nine NA subtypes, of which 23 lineages subsequently diverged. This study provides a better understanding of influenza NA lineages and their evolutionary dynamics, which may facilitate early detection of newly emerging influenza viruses and thus improve influenza surveillance.</p></div

The evolutionary dynamics of influenza neuraminidase (NA) over time.

<p>The lineages from different hosts are colored, with the emergence times of the lineages represented by the horizontal positions of squared boxes and the mean substitution rates depicted by the degree of line thickness. Note that within 2A there are five swine clusters.</p