915 research outputs found
Role of the Subunits Interactions in the Conformational Transitions in Adult Human Hemoglobin: an Explicit Solvent Molecular Dynamics Study
Hemoglobin exhibits allosteric structural changes upon ligand binding due to
the dynamic interactions between the ligand binding sites, the amino acids
residues and some other solutes present under physiological conditions. In the
present study, the dynamical and quaternary structural changes occurring in two
unligated (deoxy-) T structures, and two fully ligated (oxy-) R, R2 structures
of adult human hemoglobin were investigated with molecular dynamics. It is
shown that, in the sub-microsecond time scale, there is no marked difference in
the global dynamics of the amino acids residues in both the oxy- and the deoxy-
forms of the individual structures. In addition, the R, R2 are relatively
stable and do not present quaternary conformational changes within the time
scale of our simulations while the T structure is dynamically more flexible and
exhibited the T\rightarrow R quaternary conformational transition, which is
propagated by the relative rotation of the residues at the {\alpha}1{\beta}2
and {\alpha}2{\beta}1 interface.Comment: Reprinted (adapted) with permission from J. Phys. Chem. B
DOI:10.1021/jp3022908. Copyright (2012) American Chemical Societ
Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles
The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society
Outer-Sphere Contributions to the Electronic Structure of Type Zero Copper Proteins
Bioinorganic canon states that active-site
thiolate coordination promotes rapid electron transfer (ET)
to and from type 1 copper proteins. In recent work, we have
found that copper ET sites in proteins also can be constructed
without thiolate ligation (called “type zero” sites). Here we
report multifrequency electron paramagnetic resonance
(EPR), magnetic circular dichroism (MCD), and nuclear
magnetic resonance (NMR) spectroscopic data together with
density functional theory (DFT) and spectroscopy-oriented
configuration interaction (SORCI) calculations for type zero Pseudomonas aeruginosa azurin variants. Wild-type (type 1) and type
zero copper centers experience virtually identical ligand fields. Moreover, O-donor covalency is enhanced in type zero centers
relative that in the C112D (type 2) protein. At the same time, N-donor covalency is reduced in a similar fashion to type 1
centers. QM/MM and SORCI calculations show that the electronic structures of type zero and type 2 are intimately linked to the
orientation and coordination mode of the carboxylate ligand, which in turn is influenced by outer-sphere hydrogen bonding
Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses
Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21-mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR-mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components
T-Analyst: a program for efficient analysis of protein conformational changes by torsion angles
T-Analyst is a user-friendly computer program for analyzing trajectories from molecular modeling. Instead of using Cartesian coordinates for protein conformational analysis, T-Analyst is based on internal bond-angle-torsion coordinates in which internal torsion angle movements, such as side-chain rotations, can be easily detected. The program computes entropy and automatically detects and corrects angle periodicity to produce accurate rotameric states of dihedrals. It also clusters multiple conformations and detects dihedral rotations that contribute hinge-like motions. Correlated motions between selected dihedrals can also be observed from the correlation map. T-Analyst focuses on showing changes in protein flexibility between different states and selecting representative protein conformations for molecular docking studies. The program is provided with instructions and full source code in Perl
Актуальність впровадження систем газового обліку в сучасних умовах
Free energy calculation has long been an important goal for molecular dynamics simulation and force field development, but historically it has been challenged by limited performance, accuracy, and creation of topologies for arbitrary small molecules. This has made it difficult to systematically compare different sets of parameters to improve existing force fields, but in the past few years several authors have developed increasingly automated procedures to generate parameters for force fields such as Amber, CHARMM, and OPLS. Here, we present a new framework that enables fully automated generation of GROMACS topologies for any of these force fields and an automated setup for parallel adaptive optimization of high-throughput free energy calculation by adjusting lambda point placement on the fly. As a small example of this automated pipeline, we have calculated solvation free energies of 50 different small molecules using the GAFF, OPLS-AA, and CGenFF force fields and four different water models, and by including the often neglected polarization costs, we show that the common charge models are somewhat underpolarized.QC 20150505</p
Virus Capsid Dissolution Studied by Microsecond Molecular Dynamics Simulations
Dissolution of many plant viruses is thought to start with swelling of the capsid caused by calcium removal following infection, but no high-resolution structures of swollen capsids exist. Here we have used microsecond all-atom molecular simulations to describe the dynamics of the capsid of satellite tobacco necrosis virus with and without the 92 structural calcium ions. The capsid expanded 2.5% upon removal of the calcium, in good agreement with experimental estimates. The water permeability of the native capsid was similar to that of a phospholipid membrane, but the permeability increased 10-fold after removing the calcium, predominantly between the 2-fold and 3-fold related subunits. The two calcium binding sites close to the icosahedral 3-fold symmetry axis were pivotal in the expansion and capsid-opening process, while the binding site on the 5-fold axis changed little structurally. These findings suggest that the dissociation of the capsid is initiated at the 3-fold axis
Surface behavior of amphiphiles in aqueous solution: a comparison between different pentanol isomers
The nucleotide addition cycle of RNA polymerase is controlled by two molecular hinges in the Bridge Helix domain
Abstract Background Cellular RNA polymerases (RNAPs) are complex molecular machines that combine catalysis with concerted conformational changes in the active center. Previous work showed that kinking of a hinge region near the C-terminus of the Bridge Helix (BH-HC) plays a critical role in controlling the catalytic rate. Results Here, new evidence for the existence of an additional hinge region in the amino-terminal portion of the Bridge Helix domain (BH-HN) is presented. The nanomechanical properties of BH-HN emerge as a direct consequence of the highly conserved primary amino acid sequence. Mutations that are predicted to influence its flexibility cause corresponding changes in the rate of the nucleotide addition cycle (NAC). BH-HN displays functional properties that are distinct from BH-HC, suggesting that conformational changes in the Bridge Helix control the NAC via two independent mechanisms. Conclusions The properties of two distinct molecular hinges in the Bridge Helix of RNAP determine the functional contribution of this domain to key stages of the NAC by coordinating conformational changes in surrounding domains.</p
Variational Approach to Molecular Kinetics
The eigenvalues and eigenvectors of the molecular dynamics propagator (or transfer operator) contain the essential information about the molecular thermodynamics and kinetics. This includes the stationary distribution, the metastable states, and state-to-state transition rates. Here, we present a variational approach for computing these dominant eigenvalues and eigenvectors. This approach is analogous the variational approach used for computing stationary states in quantum mechanics. A corresponding method of linear variation is formulated. It is shown that the matrices needed for the linear variation method are correlation matrices that can be estimated from simple MD simulations for a given basis set. The method proposed here is thus to first define a basis set able to capture the relevant conformational transitions, then compute the respective correlation matrices, and then to compute their dominant eigenvalues and eigenvectors, thus obtaining the key ingredients of the slow kinetics
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