Bound-state Structures Research Articles

Quantum Chemistry-Based Protein-Protein Docking without Empirical Parameters.

This study developed a novel protein-protein docking approach based on quantum chemistry. To judge the appropriateness of complex structures, we introduced two criterion values, EV1 and EV2, computed using the fragment molecular orbital method without any empirical parameters. These criterion values enable us to search complex structures in which patterns of the electrostatic potential of the two proteins are optimally aligned at their interface. The performance of our method was validated using 53 complexes in a benchmark set provided for protein-protein docking. When employing bound state structures, docking success rates reached 64% for EV1 and 76% for EV2. On the other hand, when employing unbound state structures, docking success rates reached 13% for EV1 and 17% for EV2.

Plunger gate effects on magneto transport in double-top gate spin-orbit devices

A propagation matrix method is used to investigate the quantum conductance of an n-type double-top gate device under a strong Rashba-Zeeman coupling interaction. The effects of a plunger gate potential and the total top gate length on the magneto conduction properties are investigated. Transcendental equations and analytical formulas are derived to accurately predict the resonance state and hole-like bound state structures. Furthermore, the effect of the distance of the two top gates from the plunger gate is examined for both symmetric and asymmetric structures. The analytical technique employed in this study provides an accurate and reliable approach for calculating the conductance of the quantum transport and is therefore beneficial for the design of n-type semiconductor devices.

Analysis of a preQ1-I riboswitch in effector-free and bound states reveals a metabolite-programmed nucleobase-stacking spine that controls gene regulation.

Riboswitches are structured RNA motifs that recognize metabolites to alter the conformations of downstream sequences, leading to gene regulation. To investigate this molecular framework, we determined crystal structures of a preQ1-I riboswitch in effector-free and bound states at 2.00 Å and 2.65 Å-resolution. Both pseudoknots exhibited the elusive L2 loop, which displayed distinct conformations. Conversely, the Shine-Dalgarno sequence (SDS) in the S2 helix of each structure remained unbroken. The expectation that the effector-free state should expose the SDS prompted us to conduct solution experiments to delineate environmental changes to specific nucleobases in response to preQ1. We then used nudged elastic band computational methods to derive conformational-change pathways linking the crystallographically-determined effector-free and bound-state structures. Pathways featured: (i) unstacking and unpairing of L2 and S2 nucleobases without preQ1—exposing the SDS for translation and (ii) stacking and pairing L2 and S2 nucleobases with preQ1—sequestering the SDS. Our results reveal how preQ1 binding reorganizes L2 into a nucleobase-stacking spine that sequesters the SDS, linking effector recognition to biological function. The generality of stacking spines as conduits for effector-dependent, interdomain communication is discussed in light of their existence in adenine riboswitches, as well as the turnip yellow mosaic virus ribosome sensor.

Structure and Decay at Rapid Proton Capture Waiting Points

We investigate the region of the nuclear chart around $A \simeq 70$ from a three-body perspective, where we compute reaction rates for the radiative capture of two protons. One key quantity is here the photon dissociation cross section for the inverse process where two protons are liberated from the borromean nucleus by photon bombardment. We find a number of peaks at low photon energy in this cross section where each peak is located at the energy corresponding to population of a three-body resonance. Thus, for these energies the decay or capture processes proceed through these resonances. However, the next step in the dissociation process still has the option of following several paths, that is either sequential decay by emission of one proton at a time with an intermediate two-body resonance as stepping stone, or direct decay into the continuum of both protons simultaneously. The astrophysical reaction rate is obtained by folding of the cross section as function of energy with the occupation probability for a Maxwell-Boltzmann temperature distribution. The reaction rate is then a function of temperature, and of course depending on the underlying three-body bound state and resonance structures. We show that a very simple formula at low temperature reproduces the elaborate numerically computed reaction rate.

Rapid thermal co-annihilation through bound states in QCD

The co-annihilation rate of heavy particles close to thermal equilibrium, which plays a role in many classic dark matter scenarios, can be "simulated" in QCD by considering the pair annihilation rate of a heavy quark and antiquark at a temperature of a few hundred MeV. We show that the so-called Sommerfeld factors, parameterizing the rate, can be defined and measured non-perturbatively within the NRQCD framework. Lattice measurements indicate a modest suppression in the octet channel, in reasonable agreement with perturbation theory, and a large enhancement in the singlet channel, much above the perturbative prediction. The additional enhancement is suggested to originate from bound state formation and subsequent decay. Making use of a Green's function based method to incorporate thermal corrections in perturbative co-annihilation rate computations, we show that qualitative agreement with lattice data can be found once thermally broadened bound states are accounted for. We suggest that our formalism may also be applicable to specific dark matter models which have complicated bound state structures.

Characterization of the Free State Ensemble of the CoRNR Box Motif by Molecular Dynamics Simulations

Intrinsically disordered proteins (IDPs) and regions are highly prevalent in eukaryotic proteomes, and like folded proteins, they perform essential biological functions. Interaction sites in folded proteins are generally formed by tertiary structures, whereas IDPs use short segments called linear motifs (LMs). Despite their short length and lack of stable structure, LMs may have considerable structural propensities, which often resemble bound-state conformations with targets. Structural data is crucial for understanding the molecular basis of protein interactions and development of targeted pharmaceuticals, but IDPs present considerable challenges to experimental techniques. As a result, IDPs are largely underrepresented in the Protein Data Bank. In the face of experimental challenges, molecular dynamics (MD) simulations have proven to be a useful tool for structural characterization of IDPs. Here, the free state ensemble of the nuclear receptor corepressor 1 (NCOR1) CoRNR box 3 motif, which is important for binding to nuclear receptors to control gene expression, is studied using MD simulations of a total of 8 μs. Transitions between disordered and α-helical conformations resembling a bound-state structure were observed throughout the trajectory, indicating that the motif may have a natural conformational bias toward bound-state structures. The data shows that the disordered and folded populations are separated by a low energy (4-6 kJ/mol) barrier, and the presence of off-pathway intermediates, leading to a C-terminally folded species that cannot efficiently transition into a completely folded conformation. Structural transitions and folding pathways within the free state ensemble were well-described by principal component analysis (PCA) of the peptide backbone dihedral angles, with the analysis providing insight for increasing structural homogeneity of the ensemble.

The Importance of Intrinsic Order in a Disordered Protein Ligand

The Importance of Intrinsic Order in a Disordered Protein Ligand

Re-Docking Scheme for Generating Near-Native Protein Complexes by Assembling Residue Interaction Fingerprints

Interaction profile method is a useful method for processing rigid-body docking. After the docking process, the resulting set of docking poses could be classified by calculating similarities among them using these interaction profiles to search for near-native poses. However, there are some cases where the near-native poses are not included in this set of docking poses even when the bound-state structures are used. Therefore, we have developed a method for generating near-native docking poses by introducing a re-docking process. We devised a method for calculating the profile of interaction fingerprints by assembling protein complexes after determining certain core-protein complexes. For our analysis, we used 44 bound-state protein complexes selected from the ZDOCK benchmark dataset ver. 2.0, including some protein pairs none of which generated near-native poses in the docking process. Consequently, after the re-docking process we obtained profiles of interaction fingerprints, some of which yielded near-native poses. The re-docking process involved searching for possible docking poses in a restricted area using the profile of interaction fingerprints. If the profile includes interactions identical to those in the native complex, we obtained near-native docking poses. Accordingly, near-native poses were obtained for all bound-state protein complexes examined here. Application of interaction fingerprints to the re-docking process yielded structures with more native interactions, even when a docking pose, obtained following the initial docking process, contained only a small number of native amino acid interactions. Thus, utilization of the profile of interaction fingerprints in the re-docking process yielded more near-native poses.

De Novo Generation of Bound Structures for an Intrinsically Disordered Protein using Only Alpha Carbon Chemical Shifts

Intrinsically disordered proteins (IDPs) challenge our traditional notions of protein structure/function relationships because they are highly dynamic in their native state and do not form tertiary structures. To design new drugs for IDPs it is essential to generate realistic structural ensembles for these proteins. We have recently developed a method called broad ensemble generation with re-weighting (BEGR) where a million or more diverse IDP structures are generated and then re-weighted to fit experimental data. Results show that bound state structures of the disordered p53 transactivation domain (p53TAD) are reproducibly generated, even though the BEGR method is using experimental data for unbound p53TAD. These bound state structures were found for wild type p53TAD and a mutant that increases the transient helical secondary structure of one of the binding sites using only the alpha carbon chemical shift data.

Free and bound state structures of 6- O-methyl homoerythromycins and epitope mapping of their interactions with ribosomes

The solution and solid state conformations of several 6- O-methyl homoerythromycins 1– 4 were studied using a combination of X-ray crystallography, NMR spectroscopy and molecular modelling calculations. In the solid state 1 was found to exist as the two independent molecules with similar structures termed 3- endo-folded-out. In solution a significant conformational flexibility was noticed especially in the C2 to C5 region. The compounds 1 and 2 unlike 14-membered macrolides adopted the 3- endo-folded-out conformation while 3 and 4 existed in the classical folded-out conformation. TrNOESY and STD experiments showed that 1 and 2 bound to the Escherichia coli ribosome while 3 and 4, lacking the cladinose sugar, did not exhibit binding activities, this being in accordance with biochemical data. The bound conformations were found to be very similar to the free ones, some small differences were observed and discussed. The STD experiments provided evidence on binding epitopes. The structural parts of 1 and 2 in close contact with ribosome were similar, however the degree of saturation transfer was higher for 2. The differences between tr-NOE data and STD enhancements in 1 and 2 arouse as a consequence of structural changes upon binding and a closer proximity of 2 to the ribosome surface. An understanding of the molecular mechanisms involved in the interaction of macrolides with ribosomes can help in developing strategies aiming at design of potential inhibitors.

Generation of parabolic bound pulses from a Yb-fiber laser

We report the observation of self-similar propagation of bound-state pulses in an ytterbium-doped double-clad fiber laser. A bound state of two positively chirped parabolic pulses with 5.4 ps duration separated by 14.9 ps is obtained, with 1.7 nJ of energy per pulse. These pulses are extra-cavity compressed to 100 fs. For higher pumping power and a different setting of the intra-cavity polarization controllers, the laser generates a bound state of three chirped parabolic pulses with different time separations and more than 1.5 nJ energy per pulse. Perturbation of this bound state by decreasing pump power results in the generation of a single pulse and a two-pulse bound state both structures traveling at the same velocity along the cavity. A possible explanation of the zero relative speed by a particular phase relation of the bound states is discussed.

Presence of nonlinear excitations in DNA structure and their relationship to DNA premelting and to drug intercalation.

We propose that collectively localized nonlinear excitations (solitons) exist in DNA structure. These arise as a consequence of an intrinsic nonlinear ribose inversion instability that results in a modulated beta alternation in sugar puckering along the polymer backbone. In their bound state, soliton-antisoliton pairs contain beta premelted core regions capable of undergoing breathing motions that facilitate drug intercalation. We call such bound state structures--beta premeltons. The stability of a beta premelton is expected to reflect the collective properties of extended DNA regions and to be sensitive to temperature, pH, ionic strength and other thermodynamic factors. Its tendency to localize at specific nucleotide base sequences may serve to initiate site-specific DNA premelting and melting. We suggest that beta premeltons provide nucleation centers important for RNA polymerase-promoter recognition. Such nucleation centers could also correspond to nuclease hypersensitive sites.

Bound-state effective potential formulation of dynamical symmetry breaking

We propose an approximation procedure for studying dynamical symmetry breaking that closely parallels scalar field models of spontaneous symmetry breaking. We focus our attention on the role a deep scalar bound state plays in effecting a phase transition. We show that a viable approximation to the effective potential must contain all one-particle-reducible bound-state pole structures. This dictates a Dyson equation for the self-energy even in the simplest approximation. For theories with 4-field interactions this can reduce to a closed-form Hartree approximation. We look at trilinear interactions where the Dyson integral equation is intractible because of its nonlinearity. Without linearizing the Dyson equation we extract a bound-state contribution to the effective potential. We end up with a generalized effective potential that is a function of classical fields representing the bound state. We show that this contribution displays the proper phase transition when the theory becomes unstable due to a composite tachyon.