Self-consistent field approach to protein structure and stability

The organization of the thesis is as follows: after a short introduction (chapter 1), chapter 2 presents a review of the basic physical principle that govern protein structure and focuses on the thermodynamics as well as kinetics of protein folding and ufolding. Then chapter 3 starts with a discussion on the basic elementary interactions, which contribute, to protein structure and stability, with emphasis on the electrostatic interactions.Electrostatic interactions are described on the basis of novel approach, which uses the idea of a self-consistent field adapted from statistical mechanics. Properties such as titration curves, protein stability and pKa shifts are discussed. The main conclusions are: firstly, the calculated results are in excellent agreement with the experimental data, when the solution of Poisson-Boltzmann equation (PB) is based on the assumption that the ionized residues are seen as part of the high dielectric medium (rather than the interior of the protein molecule); Secondly, the solution of PB equation outside the protein interior, depends on local characteristics, such as the packing of chain portions around ionized residues, rather than on the detailed shape of the protein molecule. Lastly, at "natural-like" conditions the contribution of electrostatic interactions to the free energy difference between the unfolded and folded states of protein molecules is closed to zero. This indicates that the main driving forces for folding of protein molecules under these conditions are hydrophobic and backbone-backbone hydrogen bonding interactions.Chapter 4 concern the application of the theory of electrostatic interactions to the calculation of the pKa's of the 98 residue b-elicitin protein, cryptogein. Unusual in this protein is the existence of four ionized groups buried in the hydrophobic core. The NMR structure of the 98 residue b-elicitin, cryptogein was determined using and labelled protein samples. Calculation of theoretical pKa's show general agreement with experimentally determined values and is similar for both thecrystal and solution structures.In chapter 5 the topological requirement for nucleus formation of a two-state folding reaction is considered. The self-consistent field approach is used to calculate the free energy of the folding nucleus and to approximate the description of the elementary long-range interactions such as hydrogen-bonding, electrostatic and hydrophobic interactions. The local interactions between residues, which are close in sequence - as in the a-, b- or loop regions- are accounted for in an explicit form based on experimental parameters. A theoretical model for the folding of two-state small monomeric proteins is proposed. The folding problem is reduced to the question of how the folding nucleus in the transition state (TS) is formed from the ensemble of rapidly interconverting, partly structured conformations in the denatured state.It is proposed that in the denatured state the folding is energetically favored by certain highly fluctuating nucleation regions (aa b- hairpins). In experiments based on site directed mutagenesis these nucleation regions are revealed by their high F-values. In the TS folding is favored by the packing of these nucleation regions together with other portions of the polypeptide chain thus leading to a broad distribution of the F-values. As a result, the folding nucleus with native-like topology and approximately correctly formed secondary structures and loops is favored over other folding nuclei.In chapter 6 a discussion of the problem of protein fold recognition of small monomeric proteins with less than 80 residues is presented. The fold recognition strategy is based on the fact that: firstly, at the transition state level all possible protein conformations can be split out into different ensembles of similar structures. The crude characteristics of these ensembles can be described by the limited set of thermodynamically most favorable protein folds; secondly, the folding nucleus with native-like overall fold is separated from all other folding alternatives by a high free energy barrier. As a result, at the lowest free energy minimum of the TS state the protein molecules propagates toward its native state approximately isoenergetically through an ensemble of conformations of its native fold. The main contributions, which stabilize the protein folds at the TS level, are the hydrophobic and long-range backbone hydrogen bonding interactions, as well as the free energy of chain bending, and free energies of secondary structures formation.The selection of the protein architectures is mainly determined by the most general characteristics encoded in the protein sequence, such as distribution of hydrophobic and hydrophilic residues along the chain, the ability of amino acids to form different secondary structures in compact chain conformations by hydrogen bonding with their spatial or chain neighbours, and the general rules which govern the packing of the secondary structures. At the TS, the free energies of the native folds are separated by a 'gap' from the lowest free energies of the folds from structurally different packing patterns. However, the difference between the free energies of the native folds and the lowest free energies of the folds from the same packing pattern is rather small. The thesis is concluded with a summary in English, Dutch and Bulgarian.</p

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Measurement of the Lambda(b) cross section and the anti-Lambda(b) to Lambda(b) ratio with Lambda(b) to J/Psi Lambda decays in pp collisions at sqrt(s) = 7 TeV

The Lambda(b) differential production cross section and the cross section ratio anti-Lambda(b)/Lambda(b) are measured as functions of transverse momentum pt(Lambda(b)) and rapidity abs(y(Lambda(b))) in pp collisions at sqrt(s) = 7 TeV using data collected by the CMS experiment at the LHC. The measurements are based on Lambda(b) decays reconstructed in the exclusive final state J/Psi Lambda, with the subsequent decays J/Psi to an opposite-sign muon pair and Lambda to proton pion, using a data sample corresponding to an integrated luminosity of 1.9 inverse femtobarns. The product of the cross section times the branching ratio for Lambda(b) to J/Psi Lambda versus pt(Lambda(b)) falls faster than that of b mesons. The measured value of the cross section times the branching ratio for pt(Lambda(b)) > 10 GeV and abs(y(Lambda(b))) < 2.0 is 1.06 +/- 0.06 +/- 0.12 nb, and the integrated cross section ratio for anti-Lambda(b)/Lambda(b) is 1.02 +/- 0.07 +/- 0.09, where the uncertainties are statistical and systematic, respectively.Comment: Submitted to Physics Letters

Search for new physics in events with opposite-sign leptons, jets, and missing transverse energy in pp collisions at sqrt(s) = 7 TeV

A search is presented for physics beyond the standard model (BSM) in final states with a pair of opposite-sign isolated leptons accompanied by jets and missing transverse energy. The search uses LHC data recorded at a center-of-mass energy sqrt(s) = 7 TeV with the CMS detector, corresponding to an integrated luminosity of approximately 5 inverse femtobarns. Two complementary search strategies are employed. The first probes models with a specific dilepton production mechanism that leads to a characteristic kinematic edge in the dilepton mass distribution. The second strategy probes models of dilepton production with heavy, colored objects that decay to final states including invisible particles, leading to very large hadronic activity and missing transverse energy. No evidence for an event yield in excess of the standard model expectations is found. Upper limits on the BSM contributions to the signal regions are deduced from the results, which are used to exclude a region of the parameter space of the constrained minimal supersymmetric extension of the standard model. Additional information related to detector efficiencies and response is provided to allow testing specific models of BSM physics not considered in this paper.Comment: Replaced with published version. Added journal reference and DO

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters

Galaxy Clusters Associated with Short GRBs. II. Predictions for the Rate of Short GRBs in Field and Cluster Early-Type Galaxies

We determine the relative rates of short GRBs in cluster and field early-type galaxies as a function of the age probability distribution of their progenitors, P(\tau) \propto \tau^n. This analysis takes advantage of the difference in the growth of stellar mass in clusters and in the field, which arises from the combined effects of the galaxy stellar mass function, the early-type fraction, and the dependence of star formation history on mass and environment. This approach complements the use of the early- to late-type host galaxy ratio, with the added benefit that the star formation histories of early-type galaxies are simpler than those of late-type galaxies, and any systematic differences between progenitors in early- and late-type galaxies are removed. We find that the ratio varies from R(cluster)/R(field) ~ 0.5 for n = -2 to ~ 3 for n = 2. Current observations indicate a ratio of about 2, corresponding to n ~ 0 - 1. This is similar to the value inferred from the ratio of short GRBs in early- and late-type hosts, but it differs from the value of n ~ -1 for NS binaries in the Milky Way. We stress that this general approach can be easily modified with improved knowledge of the effects of environment and mass on the build-up of stellar mass, as well as the effect of globular clusters on the short GRB rate. It can also be used to assess the age distribution of Type Ia supernova progenitors.Comment: ApJ accepted versio

Search for leptophobic Z ' bosons decaying into four-lepton final states in proton-proton collisions at root s=8 TeV

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Search for black holes and other new phenomena in high-multiplicity final states in proton-proton collisions at root s=13 TeV

Peer reviewe

Search for heavy resonances decaying into a vector boson and a Higgs boson in final states with charged leptons, neutrinos, and b quarks

Peer reviewe