molecular dynamics calculations
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Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.Communicated by Ramaswamy H. Sarma.
Formation of transient complexes of cytochrome P450 (P450) with another protein of the endoplasmic reticulum membrane, cytochrome b5 (cyt b5), dictates the catalytic activities of several P450s. Therefore, we examined formation and binding modes of the complex of human P450 1A2 with cyt b5. Docking of soluble domains of these proteins was performed using an information-driven flexible docking approach implemented in HADDOCK. Stabilities of the five unique binding modes of the P450 1A2-cyt b5 complex yielded by HADDOCK were evaluated using explicit 10 ns molecular dynamics (MD) simulations in aqueous solution. Further, steered MD was used to compare the stability of the individual P450 1A2-cyt b5 binding modes. The best binding mode was characterized by a T-shaped mutual orientation of the porphyrin rings and a 10.7 Å distance between the two redox centers, thus satisfying the condition for a fast electron transfer. Mutagenesis studies and chemical cross-linking, which, in the absence of crystal structures, were previously used to deduce specific P450-cyt b5 interactions, indicated that the negatively charged convex surface of cyt b5 binds to the positively charged concave surface of P450. Our simulations further elaborate structural details of this interface, including nine ion pairs between R95, R100, R138, R362, K442, K455, and K465 side chains of P450 1A2 and E42, E43, E49, D65, D71, and heme propionates of cyt b5. The universal heme-centric system of internal coordinates was proposed to facilitate consistent classification of the orientation of the two porphyrins in any protein complex.
We combined atomistic molecular-dynamics simulations with quantum-mechanical calculations to investigate the sequence dependence of the stretching behavior of duplex DNA. Our combined quantum-mechanical/molecular-mechanical approach demonstrates that molecular-mechanical force fields are able to describe both the backbone and base-base interactions within the highly distorted nucleic acid structures produced by stretching the DNA from the 5' ends, which include conformations containing disassociated basepairs, just as well as these force fields describe relaxed DNA conformations. The molecular-dynamics simulations indicate that the force-induced melting pathway is sequence-dependent and is influenced by the availability of noncanonical hydrogen-bond interactions that can assist the disassociation of the DNA basepairs. The biological implications of these results are discussed. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
The serine/threonine protein phosphatase type 5 (PP5) is a promising target for designing new antitumor drugs. This enzyme is a member of the PPP phosphatases gene family, which catalyzes a dephosphorylation reaction: a regulatory process in the signal transduction pathway that controls various biological processes. The aim of this work is to study and compare the inhibition of PP5 by ten cantharidin-like inhibitors in order to bring about contributions relevant to the better comprehension of their inhibitory activity. In this theoretical investigation, we used molecular dynamics techniques to understand the role of key interactions that occur in the protein active site; QM calculations were employed to study the interaction mode of these inhibitors in the enzyme. In addition, atoms in molecules (AIM) calculations were carried out to characterize the chemical bonds among the atoms involved and investigate the orbital interactions with their respective energy values. The obtained results suggest that the Arg275, Asn303, His304, His352, Arg400, His427, Glu428, Val429, Tyr451, and Phe446 residues favorably contribute to the interactions between inhibitors and PP5. However, the Asp271 and Asp244 amino acid residues do not favor such interactions for some inhibitors. Through the QM calculations, we can suggest that the reactional energy of the coordination mechanism of these inhibitors in the PP5 active site is quite important and is responsible for the inhibitory activity. The AIM technique employed in this work was essential to get a better comprehension of the transition states acquired from the mechanism simulation. This work offers insights of how cantharidin-like inhibitors interact with human PP5, potentially allowing the design of more specific and even less cytotoxic drugs for cancer treatments. Graphical Abstract Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system.
- MeSH
- hořčík chemie MeSH
- inhibitory enzymů farmakologie MeSH
- jaderné proteiny antagonisté a inhibitory chemie MeSH
- kantharidin analogy a deriváty chemie farmakologie MeSH
- katalytická doména MeSH
- kationty dvojmocné chemie MeSH
- lidé MeSH
- proteinfosfatasy antagonisté a inhibitory chemie MeSH
- racionální návrh léčiv MeSH
- simulace molekulární dynamiky * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Ab initio and molecular simulation methods were used in calculations of the neutral individual betulin molecule, and molecular simulations were used to optimize the betulin molecule immersed in various amounts of water. Individual betulin was optimized in different force fields to find the one exhibiting best agreement with ab initio calculations obtained in the Gaussian03 program. Dihedral torsions of active groups of betulin were determined for both procedures, and related calculated structures were compared successfully. The selected force field was used for subsequent optimization of betulin in a water environment, and a conformational search was performed using quench molecular dynamics. The total energies of betulin and its interactions in water bulk were calculated, and the influence of water on betulin structure was investigated.
In this study, interactions of selected monosaccharides with the Pseudomonas aeruginosa Lectin II (PA-IIL) are analyzed in detail. An interesting feature of the PA-IIL binding is that the monosaccharide is interacting via two calcium ions and the binding is unusually strong for protein-saccharide interaction. We have used Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) and normal mode analysis to calculate the free energy of binding. The impact of intramolecular hydrogen bond network for the lectin/monosaccharide interaction is also analyzed.
- MeSH
- bakteriální adheziny chemie metabolismus MeSH
- entropie MeSH
- konformace proteinů MeSH
- konformace sacharidů MeSH
- lektiny chemie metabolismus MeSH
- monosacharidy chemie metabolismus MeSH
- Pseudomonas aeruginosa MeSH
- simulace molekulární dynamiky MeSH
- statická elektřina MeSH
- vápník metabolismus MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Sequence dependence of (13) C and (15) N chemical shifts in the receiver domain of CKI1 protein from Arabidopsis thaliana, CKI1RD , and its complexed form, CKI1RD •Mg(2+), was studied by means of MD/DFT calculations. MD simulations of a 20-ns production run length were performed. Nine explicitly hydrated structures of increasing complexity were explored, up to a 40-amino-acid structure. The size of the model necessary depended on the type of nucleus, the type of amino acid and its sequence neighbors, other spatially close amino acids, and the orientation of amino acid NH groups and their surface/interior position. Using models covering a 10 and a 15 Å environment of Mg(2+), a semi-quantitative agreement has been obtained between experiment and theory for the V67-I73 sequence. The influence of Mg(2+) binding was described better by the 15 Å as compared to the 10 Å model. Thirteen chemical shifts were analyzed in terms of the effect of Mg(2+) insertion and geometry preparation. The effect of geometry was significant and opposite in sign to the effect of Mg(2+) binding. The strongest individual effects were found for (15) N of D70, S74, and V68, where the electrostatics dominated; for (13) Cβ of D69 and (15) N of K76, where the influences were equal, and for (13) Cα of F72 and (13) Cβ of K76, where the geometry adjustment dominated. A partial correlation between dominant geometry influence and torsion angle shifts upon the coordination has been observed.
- MeSH
- hořčík chemie MeSH
- izotopy dusíku chemie MeSH
- izotopy uhlíku chemie MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- proteinkinasy chemie MeSH
- proteinové domény MeSH
- proteiny huseníčku chemie MeSH
- simulace molekulární dynamiky MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Oxidatively-generated interstrand cross-links rank among the most deleterious DNA lesions. They originate from abasic sites, whose aldehyde group can form a covalent adduct after condensation with the exocyclic amino group of purines, sometimes with remarkably high yields. We use explicit solvent molecular dynamics simulations to unravel the structures and mechanical properties of two DNA sequences containing an interstrand cross-link. Our simulations palliate the absence of experimental structural and stiffness information for such DNA lesions and provide an unprecedented insight into the DNA embedding of lesions that represent a major challenge for DNA replication, transcription and gene regulation by preventing strand separation. Our results based on quantum chemical calculations also suggest that the embedding of the ICL within the duplex can tune the reaction profile, and hence can be responsible for the high difference in yields of formation.
Clusters of a solute and a few solvent molecules obtained from molecular dynamics (MD) are a powerful tool to study solvation effects by advanced quantum chemical (QC) methods. For spectroscopic properties strongly dependent on the solvation, however, a large number of clusters are needed for a good convergence. In this work, a parallel variable selection (PVS) method is proposed that in some cases efficiently reduces the number of clusters needed for the averaging. The mass, charge, or atomic density MD distributions are used as a secondary variable to preselect the most probable cluster geometries used for averaging of solute spectral properties. When applied to nuclear magnetic resonance chemical shift of a model alcohol, the method allowed one to significantly reduce the total computational time, by a factor of 10. Even larger savings were achieved for the modeling of Raman and Raman optical activity spectra of (S)-lactamide molecule dissolved in water. The results thus suggest that the PVS method can be generally used for simulations of spectroscopic properties of solvated molecules and makes multiscale MD/QC computations more affordable.
Abstract Aromatic stacking of nucleic acid bases is one of the key players in determining the structure and dynamics of nucleic acids. The arrangement of nucleic acid bases with extensive overlap of their aromatic rings gave rise to numerous often contradictory suggestions about the physical origins of stacking and the possible role of delocalized electrons in stacked aromatic π systems, leading to some confusion about the issue. The recent advance of computer hardware and software finally allowed the application of state of the art quantum-mechanical approaches with inclusion of electron correlation effects to study aromatic base stacking, now providing an ultimitate qualitative description of the phenomenon. Base stacking is determined by an interplay of the three most commonly encountered molecular interactions: dispersion attraction, electrostatic interaction, and short-range repulsion. Unusual (aromatic- stacking specific) energy contributions were in fact not evidenced and are not necessary to describe stacking. The currently used simple empirical potential form, relying on atom-centered constant point charges and Lennard-Jones van der Waals terms, is entirely able to reproduce the essential features of base stacking. Thus, we can conclude that base stacking is in principle one of the best described interactions in current molecular modeling and it allows to study base stacking in DNA using large-scale classical molecular dynamics simulations. Neglect of cooperativity of stacking appears to be the most serious approximation of the currently used force field form. This review summarizes recent developments in the field. It is written for an audience that is not necessarily expert in computational quantum chemistry and follows up on our previous contribution (Sponer et. al., J. Biomol. Struct. Dyn. 14, 117, (1997)). First, the applied methodology, its accuracy, and the physical nature of base stacking is briefly overviewed, including a comment on the accuracy of other molecular orbital methods and force fields. Then, base stacking is contrasted with hydrogen bonding, the other dominant force in nucleic acid structure. The sequence dependence and cooperativity of base stacking is commented on, and finally a brief introduction into recent progress in large-scale molecular dynamics simulations of nucleic acids is provided. Using four stranded DNA assemblies as an example, we demonstrate the efficacy of current molecular dynamics techniques that utilize refined and verified force fields in the study of stacking in nucleic acid molecules.
