1,720,997 research outputs found
Effective yet Reliable Computation of EPR Spectra in Solution by a QM/MM Approach: Interplay between Electrostatics and Non-electrostatic Effects
Full text linkIn this paper, we have extended to the calculation of hyperfine coupling constants, the model recently proposed by some of the present authors
[Giovannini et al., J. Chem. Theory Comput. 13, 4854–4870 (2017)] to include Pauli repulsion and dispersion effects in Quantum Mechanical/
Molecular Mechanics (QM/MM) approaches. The peculiarity of the proposed approach stands in the fact that repulsion/dispersion
contributions are explicitly introduced in the QM Hamiltonian. Therefore, such terms not only enter the evaluation of energetic properties
but also propagate to molecular properties and spectra. A novel parametrization of the electrostatic fluctuating charge force field has
been developed, thus allowing a quantitative reproduction of reference QM interaction energies. Such a parametrization has been then tested
against the prediction of EPR parameters of prototypical nitroxide radicals in aqueous solutions
Mechanistic insights into metal ions transit through threefold ferritin channel
No full textBackground: The mechanism of how the hydrophilic threefold channel (C3) of ferritin nanocages facilitates diffusion of diverse metal ions into the internal cavity remains poorly explored. Methods: Computational modeling and free energy estimations were carried out on R. catesbeiana H ́ ferritin. Transit features and associated energetics for Fe 2+ , Mg 2+ , Zn 2+ ions through the C3 channel have been examined. Results: We highlight that iron conduction requires the involvement of two Fe 2+ ions in the channel. In such doubly occupied configuration, as observed in X-ray structures, Fe 2+ is displaced from the internal site (stabilized by D127) at lower energetic cost. Moreover, comparison of Fe 2+ , Mg 2+ and Zn 2+ transit features shows that E130 geometric constriction provides not only an electrostatic anchor to the incoming ions but also differentially influence their diffusion kinetics. Conclusions: Overall, the study provides insights into Fe 2+ entry mechanism and characteristic features of metal-protein interactions that influence the metal ions passage. The dynamics data suggest that E130 may act as a metal selectivity gate. This implicates an ion-specific entry mechanism through the channel with the distinct diffusion kinetics being the discriminating factor. General Significance: Ferritin nanocages not only act as biological iron reservoirs but also have gained importance in material science as template scaffolds for synthesizing metal nanoparticles. This study provides mechanistic understanding on the conduction of different metal ions through the channel
Boundary condition effects on the dynamic and electric properties of hydration layers
No full textWater solvation has a central role in several biochemical processes ranging from protein folding to biomolecular recognition and enzyme catalysis. Because of its importance, the structure and dynamics of hydration layers around biological macromolecules have been the targets of a great number of experimental and computational studies. In the present contribution, we have investigated the effects of periodic boundary conditions (PBCs), as used in conjunction with molecular dynamics (MD) simulations, on the dynamic and electric properties of water layers. In particular, we have systematically performed MD simulations of neat water and biomolecules in aqueous solutions by imposing a different external dielectric constant, a generally overlooked parameter in PBC simulations. The effect of the system size has also been addressed. Overall, our results consistently indicate that the dipole moment properties of water layers, and specifically the dipole moment fluctuations and the reorientational correlation functions, can be sensitive to the choice of the external boundary conditions, whereas other molecular properties, such as the self-diffusion coefficient and the reorientational relaxation times, are not affected. We think that our investigation may help to assess appropriate simulation conditions for modeling the aqueous environment of relevant biochemical systems and processes
Introducing an artificial photo-switch into a biological pore: A model study of an engineered α-hemolysin
No full textIn recent years, engineered biological pores responsive to external stimuli have been fruitfully used for various biotechnological applications. Moreover, the strategy of tethering photo-switchable moieties into biomolecules has provided an unprecedented temporal control of purposely designed nanodevices, as demonstrated, for example, by the light-mediated regulation of the activity of enzymes and biochannels. Inspired by these advancements, we propose here a de novo designed nanodevice featuring the α-hemolysin (αHL) membrane channel purposely functionalized by an artificial "on/off" molecular switch. The switch, which is based on the photo-isomerization of the azobenzene moiety, introduces a smart nano-valve into the natural non-gated pore to confer tunable transport properties. We validated through molecular dynamics simulations and free energy calculations the effective inter-conversion of the engineered αHL pore between two configurations corresponding to an "open" and a "closed" form. The reported switchable translocation of a single-stranded DNA fragment under applied voltage supports the promising capabilities of this nanopore prototype in view of molecular sensing, detection and delivery applications at single-molecule level
Organic solvent simulations under non-periodic boundary conditions: A library of effective potentials for the GLOB model
No full textChain length, temperature and solvent effects on the structural properties of alpha-aminoisobutyric acid homooligopeptides
No full textNon-coded alpha-amino acids, originally exploited by nature, have been successfully reproduced by recent synthetic strategies to confer special structural and functional properties to small peptides. The most known and well-studied atypical residue is alpha-aminoisobutyric acid (Aib), which is contained in a fairly large number of peptides with known antibiotic effects. Here, we report on a molecular dynamics (MD) study of a series of homooligopeptides based on alpha-aminoisobutyric acid (Aib) with increasing length (Ac-(Aib)(n)-NMe, n = 5, 6, 7 and 10) and at various temperatures, employing a recent extension of the AMBER force field tailored for the Aib residue. Solvent effects have been analyzed by comparative MD simulations of a heptapeptide in water and dimethylsulfoxide at different temperatures. Our results show that the preference for the 3(10)- and/or alpha-helix structures, which typically characterize Aib based peptides, is finely tuned by several factors including the chain length, temperature and solvent nature. While the transitions between intra-molecular i -> i + 3 and i -> i + 4 hydrogen bonds characterizing 3(10) and alpha-helices, respectively, are rather fast in small peptides (in the picosecond timescale), our analysis shows that the above physical and chemical factors modulate the relative equilibrium populations of the two helical structures. The obtained results nicely agree with available experimental data and support the use of the new force field for modeling Aib containing peptides
Pathways and Barriers for Ion Translocation through the 5-HT3A Receptor Channel.
Full text linkPentameric ligand gated ion channels (pLGICs) are ionotropic receptors that mediate fast intercellular communications at synaptic level and include either cation selective (e.g., nAChR and 5-HT3) or anion selective (e.g., GlyR, GABAA and GluCl) membrane channels. Among others, 5-HT3 is one of the most studied members, since its first cloning back in 1991, and a large number of studies have successfully pinpointed protein residues critical for its activation and channel gating. In addition, 5-HT3 is also the target of a few pharmacological treatments due to the demonstrated benefits of its modulation in clinical trials. Nonetheless, a detailed molecular analysis of important protein features, such as the origin of its ion selectivity and the rather low conductance as compared to other channel homologues, has been unfeasible until the recent crystallization of the mouse 5-HT3A receptor. Here, we present extended molecular dynamics simulations and free energy calculations of the whole 5-HT3A protein with the aim of better understanding its ion transport properties, such as the pathways for ion permeation into the receptor body and the complex nature of the selectivity filter. Our investigation unravels previously unpredicted structural features of the 5-HT3A receptor, such as the existence of alternative intersubunit pathways for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. Moreover, our study offers a molecular interpretation of the role played by an arginine triplet located in the intracellular domain on determining the characteristic low conductance of the 5-HT3A receptor, as evidenced in previous experiments. In view of these results, possible implications on other members of the superfamily are suggested
Distinct dynamical features of plasmodial and human HSP70-HSP110 highlight the divergence in their chaperone-assisted protein folding
No full textHSP70 and its evolutionarily diverged co-chaperone HSP110, forms an important node in protein folding cascade. How these proteins maintain the aggregation-prone proteome of malaria parasite in functional state remains underexplored, in contrast to its human orthologs. In this study, we have probed into conformational dynamics of plasmodial HSP70 and HSP110 through multiple μs MD-simulations (ATP-state) and compared with their respective human counterparts. Simulations covered sampling of 3.4 and 2.8 μs for HSP70 and HSP110, respectively, for parasite and human orthologs. We provide a comprehensive description of the dynamic behaviors that characterize the systems and also introduce a parameter for quantifying protein rigidity. For HSP70, the interspecies comparison reveals enhanced flexibility in IA and IB subdomain within the conserved NBD, lesser solvent accessibility of the interdomain linker and distinct dynamics of the SBDβ of Pf HSP70 in comparison to Hs HSP70. In the case of HSP110, notable contrast in the dynamics of NBD, SBDβ and SBDα was observed between parasite and human ortholog. Although HSP70 and HSP110 are members of the same superfamily, we identified specific differences in the subdomain contacts in NBD, linker properties and interdomain movements in their human and parasite orthologs. Our study suggests that differences in conformational dynamics may translate into species-specific differences in the chaperoning activities of HSP70-HSP110 in the parasite and human, respectively. Dynamical features of Pf HSP70-HSP110 may contribute to the maintenance of proteostasis in the parasite during its intracellular survival in the host
Electrostatic and Structural Bases of Fe2+ Translocation through Ferritin Channels
Full text linkFerritin molecular cages are marvelous 24-mer supramolecular architectures that enable massive iron storage (>2000 iron atoms) within their inner cavity. This cavity is connected to the outer environment by two channels at C3 and C4 symmetry axes of the assembly. Ferritins can also be exploited as carriers for in vivo imaging and therapeutic applications, owing to their capability to effectively protect synthetic non-endogenous agents within the cage cavity and deliver them to targeted tissue cells without stimulating adverse immune responses. Recently, X-ray crystal structures of Fe(2+)-loaded ferritins provided important information on the pathways followed by iron ions toward the ferritin cavity and the catalytic centers within the protein. However, the specific mechanisms enabling Fe(2+) uptake through wild-type and mutant ferritin channels is largely unknown. To shed light on this question, we report extensive molecular dynamics simulations, site-directed mutagenesis, and kinetic measurements that characterize the transport properties and translocation mechanism of Fe(2+) through the two ferritin channels, using the wild-type bullfrog Rana catesbeiana H' protein and some of its variants as case studies. We describe the structural features that determine Fe(2+) translocation with atomistic detail, and we propose a putative mechanism for Fe(2+) transport through the channel at the C3 symmetry axis, which is the only iron-permeable channel in vertebrate ferritins. Our findings have important implications for understanding how ion permeation occurs, and further how it may be controlled via purposely engineered channels for novel biomedical applications based on ferritin
Assessment of Multi-Scale Approaches for Computing UV–Vis Spectra in Condensed Phases: Toward an Effective yet Reliable Integration of Variational and Perturbative QM/MM Approaches
No full textComputational simulation of UV/vis
spectra in condensed phases
can be performed starting from converged molecular dynamics (MD) simulations
and then performing quantum mechanical/molecular mechanical (QM/MM)
computations for a statistically significant number of snapshots.
However, the need of variational solutions (e.g., ONIOM/EE) for a
huge number of snapshots makes unpractical the use of state-of-the-art
QM Hamiltonians. On the other hand, the effectivity of perturbative
approaches (e.g., perturbed matrix method, PMM) comes at the price
of poor convergence for configurations strongly different from the
reference one. In this paper we introduce an integrated strategy based
on a cluster analysis of the MD snapshots. Next, a representative
configuration for each cluster is treated at the ONIOM/EE level, whereas
local fluctuations within each cluster are described at the PMM level.
Some representative systems (uracil in dimethylformamide and
in water and tyrosine zwitterion in water) are analyzed to show the
effectivity and flexibility of the proposed strategy
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