Relationship between Hot Spot Residues and Ligand Binding Hot Spots in Protein-Protein Interfaces

In the context of protein-protein interactions, the term "hot spot" refers to a residue or cluster of residues that makes a major contribution to the binding free energy, as determined by alanine scanning mutagenesis. In contrast, in pharmaceutical research, a hot spot is a site on a target protein that has high propensity for ligand binding and hence is potentially important for drug discovery. Here we examine the relationship between these two hot spot concepts by comparing alanine scanning data for a set of 15 proteins with results from mapping the protein surfaces for sites that can bind fragment-sized small molecules. We find the two types of hot spots are largely complementary; the residues protruding into hot spot regions identified by computational mapping or experimental fragment screening are almost always themselves hot spot residues as defined by alanine scanning experiments. Conversely, a residue that is found by alanine scanning to contribute little to binding rarely interacts with hot spot regions on the partner protein identified by fragment mapping. In spite of the strong correlation between the two hot spot concepts, they fundamentally differ, however. In particular, while identification of a hot spot by alanine scanning establishes the potential to generate substantial interaction energy with a binding partner, there are additional topological requirements to be a hot spot for small molecule binding. Hence, only a minority of hot spots identified by alanine scanning represent sites that are potentially useful for small inhibitor binding, and it is this subset that is identified by experimental or computational fragment screening.     

Universal stratifications and a Bertini-type theorem

A stratification of the set of critical points of a map is universal in the class of stratifications satisfying the classical Thom and Whitney-a conditions if it is the coarsest among all such stratifications. We show that a universal stratification exists if and only if the ‘canonical subbundle’ of the cotangent bundle of the source of the map (constructed via operations introduced by Glaeser) is Lagrangian. The proof relies on a new Bertini-type theorem for singular varieties proved via an intriguing use of resolution of singularities. Many examples are provided, including those of maps without universal stratifications.     

Reaction of organylxenonium(II) salts, [RXe][Y], with organyl iodides, R'I, in anhydrous HF: scope and limitation of a new synthetic approach to iodonium salts, [RR'I][Y

Perfluoroalkynylxenonium salts, [RXe][BF(4)] (R = CF(3)C≡C, (CF(3))(2)CFC≡C), reacted with organyl iodides, R'I (R' = 3-FC(6)H(4), C(6)F(5), CF(2)═CF, CF(3)CH(2); no reaction with R' = CF(3)CF(2)CF(2)) in anhydrous HF to yield the corresponding asymmetric polyfluorinated iodonium salts, [RR'I][Y]. The action of the arylxenonium salt, [C(6)F(5)Xe][BF(4)], and the cycloalkenylxenonium salt, [cyclo-1,4-C(6)F(7)Xe][AsF(6)], on 4-FC(6)H(4)I gave [C(6)F(5)(4-FC(6)H(4))I][BF(4)] and [cyclo-1,4-C(6)F(7)(4-FC(6)H(4))I][AsF(6)], respectively, besides the symmetric iodonium salt, [(4-FC(6)H(4))(2)I][Y]. But the aryl-, as well as the cycloalkenylxenonium salt, did not react with C(6)F(5)I, CF(2)═CFI, and CF(3)CH(2)I.     

A quantum chemical study of the decomposition of Keggin-structured heteropolyacids

Heterpolyacids (HPAs) demonstrate catalytic activity for oxidative and acid-catalyzed hydrocarbon conversion processes. Deactivation and thermal instability, however, have prevented their widespread use. Herein, ab initio density functional theory is used to study the thermal decomposition of the Keggin molecular HPA structure through the desorption of constitutional water molecules. The overall reaction energy and activation barrier are computed for the overall reaction HnXM12O40-->Hn-2XM12O39+H2O. and subsequently used to predict the effect of HPA composition on thermal stability. For example, the desorption of a constitutional water molecule is found to be increasingly endothermic in the order silicomolybdic acid (H4SiMo12O40)相似文献   

Size, shape, and flexibility of RNA structures

Determination of sizes and flexibilities of RNA molecules is important in understanding the nature of packing in folded structures and in elucidating interactions between RNA and DNA or proteins. Using the coordinates of the structures of RNA in the Protein Data Bank we find that the size of the folded RNA structures, measured using the radius of gyration R(G), follows the Flory scaling law, namely, R(G)=5.5N(1/3) A, where N is the number of nucleotides. The shape of RNA molecules is characterized by the asphericity Delta and the shape S parameters that are computed using the eigenvalues of the moment of inertia tensor. From the distribution of Delta, we find that a large fraction of folded RNA structures are aspherical and the distribution of S values shows that RNA molecules are prolate (S>0). The flexibility of folded structures is characterized by the persistence length l(p). By fitting the distance distribution function P(r), that is computed using the coordinates of the folded RNA, to the wormlike chain model we extracted the persistence length l(p). We find that l(p) approximately 1.5N(0.33) A which might reflect the large separation between the free energies that stabilize secondary and tertiary structures. The dependence of l(p) on N implies that the average length of helices should increase as the size of RNA grows. We also analyze packing in the structures of ribosomes (30S, 50S, and 70S) in terms of R(G), Delta, S, and l(p). The 70S and the 50S subunits are more spherical compared to most RNA molecules. The globularity in 50S is due to the presence of an unusually large number (compared to 30S subunit) of small helices that are stitched together by bulges and loops. Comparison of the shapes of the intact 70S ribosome and the constituent particles suggests that folding of the individual molecules might occur prior to assembly.     

On the orbital stability of planar periodic motions of a rigid body in the Bobylev-Steklov case

We deal with the problem of orbital stability of pendulum-like periodic motions of a heavy rigid body with a fixed point. We suppose that a mass geometry corresponds to the Bobylev-Steklov case. The stability problem is solved in nonlinear setting. In the case of small amplitude oscillations and rotations with large angular velocities the small parameter can be introduced and the problem can be investigated analytically. In the case of unspecified oscillation amplitude or rotational angular velocity the problem is reduced to analysis of stability of a fixed point of the symplectic map generated by the equations of the perturbed motion. The coefficients of the symplectic map are determined numerically. Rigorous results on the orbital stability or instability of unperturbed motion are obtained by analyzing these coefficients.     

Standard SANC modules for NLO QCD radiative corrections to single top-quark production

In this paper we present the results obtained with the newly created standard SANC modules for calculation of the NLO QCD corrections to single top-quark-production processes in s and t channels at the partonic level, as well as to top-decays. The main aim of these results is to prove the correct work of modules. A comprehensive comparison with the results of the CompHEP system is given, where possible. These modules are intended to be used in Monte Carlo generators for single top-quark-production processes at the LHC. As in our recent paper, devoted to the electroweak corrections to these processes, we study the regularization of the top-legs associated infrared divergences with the aid of the complex mass of the top quark. A comparison of QCD corrections with those computed by the conventional method is presented both for top production and for decays. For s-channel production we give an analytic proof of equivalence of the two methods in the limit of low top width.     

Design,Synthesis, and Biological Evaluation of Novel MAO-A Inhibitors Targeting Lung Cancer

Lung cancer is one of the most common causes of cancer-related deaths worldwide. Monoamine Oxidase-A (MAO-A) enzyme mediates the production of reactive oxygen species (ROS) that trigger DNA damage and oxidative injury of cells resulting in tumor initiation and progression. Available MAO-A inhibitors are used as antidepressants, however, their role as anticancer agents is still under investigation. Ligand- and structure-based drug design approaches guided the discovery and development of novel MAO-A inhibitors. A series of 1H indole-2-carboxamide derivatives was prepared and characterized using 1H-NMR, 13C-NMR, and IR. The antiproliferative effects of MAO-A inhibitors were evaluated using the cell viability assay (MTT), and MAO-A activity was evaluated using MAO-A activity assay. The presumed inhibitors significantly inhibited the growth of lung cell lines in a dose- and time dependent manner. The half maximal inhibitory concentration (IC₅₀) values of MAO-A inhibitors (S1, S2, S4, S7, and S10) were 33.37, 146.1, 208.99, 307.7, and 147.2 µM, respectively, in A549. Glide docking against MAO-A showed that the derivatives accommodate MAO-A binding cleft and engage with key binding residues. MAO-A inhibitors provide significant and consistent evidence on MAO-A activity in lung cancer and present a potential target for the development of new chemotherapeutic agents.     

Model Independent QED Corrections to the Process ep → eX

We give an exhaustive presentation of the semi-analytical approach to the model independent leptonic QED corrections to deep inelastic neutral current lepton-nucleon scattering. These corrections include photonic bremsstrahlung from and vertex corrections to the lepton current of the order φ(α) with soft photon exponentiation. A common treatment of these radiative corrections in several variables — leptonic, hadronic, mixed, Jaquet-Blondel variables — has been developed and double differential cross sections are calculated. In all sets of variables we use some structure functions, which depend on the hadronic variables and which do not have to be defined in the quark parton model. The remaining numerical integrations are twofold (for leptonic variables) or onefold (for all other variables). For the case of hadronic variables, all phase space integrals have been performed analytically. Numerical results are presented for a large kinematical range, covering fixed target as well as collider experiments at HERA or LEP⊗LHC, with a special emphasis on HERA physics.     

Reactions of triethylgermylpentafluorobenzene with some electrophilic agents

Triethylgermylpentafluorobenzene C₆F₅GeEt₃ reacts with CF₃SO₃H, HSO₃Cl, Me₃SiOSO₂Cl, chlorine, bromine, Cl₂/AlCl₃, or Br₂/AlBr₃ with cleavage of the C_aryl Ge bond. Cesium fluoride promotes electrophilic degermylation of C₆F₅GeEt₃, possibly via the intermediate formation of a tetraorganylfluorogermanate.