From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein

Unusual DNA binding modes for metal anticancer complexes

DNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes

Helical Edge Modes near Transition to Topological Insulator with Indirect Gap

Helical edge modes are characteristic of topological insulators in two dimensions. This paper demonstrates that helical edge modes remain across transitions to ordinary insulators or to semimetals under certain condition. Straight and zigzag edges are considered in a tight-binding model on square lattice. We focus on the case of indirect gap in bulk topological insulators, and obtain the spectrum of edge modes on both sides of transitions. For straight edge, the helical edge mode in topological insulators with strong particle-hole asymmetry has a reentrant region in momentum space. Edge modes show up even in ordinary insulators, but are absent in semimetals. In zigzag edge, the helical edge mode survives in both semimetals and ordinary insulators. However, the edge modes are absent inside the energy gap of ordinary insulators. All results are obtained analytically.Comment: 9 pages, 11 figure

Topological qubits in graphenelike systems

The fermion-doubling problem can be an obstacle to getting half-a-qubit in two-dimensional fermionic tight-binding models in the form of Majorana zero modes bound to the core of superconducting vortices. We argue that the number of such Majorana zero modes is determined by a Z_2 x Z_2 topological charge for a family of two-dimensional fermionic tight-binding models ranging from noncentrosymmetric materials to graphene. This charge depends on the dimension of the representation (i.e., the number of species of Dirac fermions -- where the doubling problem enters) and the parity of the Chern number induced by breaking time-reversal symmetry. We show that in graphene there are as many as ten order parameters that can be used in groups of four to change the topological number from even to odd.Comment: 5 pages; 2 figures; 1 tabl

Gi- and Gs-coupled GPCRs show different modes of G-protein binding.

More than two decades ago, the activation mechanism for the membrane-bound photoreceptor and prototypical G protein-coupled receptor (GPCR) rhodopsin was uncovered. Upon light-induced changes in ligand-receptor interaction, movement of specific transmembrane helices within the receptor opens a crevice at the cytoplasmic surface, allowing for coupling of heterotrimeric guanine nucleotide-binding proteins (G proteins). The general features of this activation mechanism are conserved across the GPCR superfamily. Nevertheless, GPCRs have selectivity for distinct G-protein family members, but the mechanism of selectivity remains elusive. Structures of GPCRs in complex with the stimulatory G protein, Gs, and an accessory nanobody to stabilize the complex have been reported, providing information on the intermolecular interactions. However, to reveal the structural selectivity filters, it will be necessary to determine GPCR-G protein structures involving other G-protein subtypes. In addition, it is important to obtain structures in the absence of a nanobody that may influence the structure. Here, we present a model for a rhodopsin-G protein complex derived from intermolecular distance constraints between the activated receptor and the inhibitory G protein, Gi, using electron paramagnetic resonance spectroscopy and spin-labeling methodologies. Molecular dynamics simulations demonstrated the overall stability of the modeled complex. In the rhodopsin-Gi complex, Gi engages rhodopsin in a manner distinct from previous GPCR-Gs structures, providing insight into specificity determinants

Effective response theory for zero energy Majorana bound states in three spatial dimensions

We propose a gravitational response theory for point defects (hedgehogs) binding Majorana zero modes in (3+1)-dimensional superconductors. Starting in 4+1 dimensions, where the point defect is extended into a line, a coupling of the bulk defect texture with the gravitational field is introduced. Diffeomorphism invariance then leads to an $SU(2)_2$ Kac-Moody current running along the defect line. The $SU(2)_2$ Kac-Moody algebra accounts for the non-Abelian nature of the zero modes in 3+1 dimensions. It is then shown to also encode the angular momentum density which permeates throughout the bulk between hedgehog-anti-hedgehog pairs.Comment: 7 pages, 3 figure

Inter-valley plasmons in graphene

The spectrum of two-dimensional (2D) plasma waves in graphene has been recently studied in the Dirac fermion model. We take into account the whole dispersion relation for graphene electrons in the tight binding approximation and the local field effects in the electrodynamic response. Near the wavevectors close to the corners of the hexagon-shaped Brillouin zone we found new low-frequency 2D plasmon modes with a linear spectrum. These "inter-valley" plasmon modes are related to the transitions between the two nearest Dirac cones.Comment: 4 pages, 2 figures; submitted in PR