force-fields
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Recent advances in polarizable force fields have revealed that major reparameterization is necessary when the polarization energy is treated explicitly. This study is focused on the torsional parameters, which are crucial for the accurate description of conformational equilibria in biomolecules. In particular, attention is paid to the influence of polarization on the (i) transferability of dihedral terms between molecules, (ii) transferability between different environments, and (iii) additivity of dihedral energies. To this end, three polarizable force fields based on the induced point dipole model designed for use in AMBER are tested, including two recent ff02 reparameterizations. Attention is paid to the contributions due to short range interactions (1-2, 1-3, and 1-4) within the four atoms defining the dihedral angle. The results show that when short range 1-2 and 1-3 polarization interactions are omitted, as for instance in ff02, the 1-4 polarization contribution is rather small and unlikely to improve the description of the torsional energy. Conversely, when screened 1-2 and 1-3 interactions are included, the polarization contribution is sizeable and shows potential to improve the transferability of parameters between different molecules and environments as well as the additivity of dihedral terms. However, to reproduce intramolecular polarization effects accurately, further fine-tuning of the short range damping of polarization is necessary.
Modelling of carbohydrate conformations is a challenging task for force field developers. Three carbohydrate force fields, namely GLYCAM06, GROMOS 45a4 and OPLS were evaluated. Free energies of different ring conformations of beta-D-glucopyranose were calculated using metadynamics in vacuum as well as in explicitly modelled water. All three force fields model the (4)C(1) conformation as the most stable by at least 6kJ/mol, as compared to other conformations. Interconversion from the (4)C(1) to any other conformation is associated with a barrier of no lower than 26kJ/mol. The free energy surface calculated in the GLYCAM06 force field is in remarkably good agreement with the recent Car-Parrinello metadynamics study. The effect of a water environment is relatively low and analogous in all tested force fields. Namely, the presence of water stabilizes the upper-left ((3,O)B) versus bottom-right (B(3,O)) area of Stoddard's plot, relative to the situation in vacuum. Comparison of free and potential surfaces is also provided for vacuum calculations.
Although current AMBER force fields are relatively accurate for canonical B-DNA, many noncanonical structures are still described incorrectly. As noncanonical motifs are attracting increasing attention due to the role they play in living organisms, further improvement is desirable. Here, we have chosen the Z-DNA molecule, which can be considered a touchstone of the universality of empirical force fields, since the noncanonical α and γ backbone conformations native to Z-DNA are also found in protein-DNA complexes, i-motif DNA, and other noncanonical DNAs. We show that spurious α/γ conformations occurring in simulations with current AMBER force fields, OL15 and bsc1, are largely due to inaccurate α/γ parametrization. Moreover, stabilization of native Z-DNA substates involving γ = trans conformations appears to be in conflict with the correct description of the canonical B-DNA structure. Because the balance of the native and spurious conformations is influenced by nonadditive effects, this is a difficult case for an additive dihedral energy scheme such as AMBER. We propose new α/γ parameters, denoted OL21, and show that they improve the stability of native α/γ Z-DNA substates while keeping the canonical DNA description virtually unchanged, thus representing a reasonable compromise within the additive force field framework. Although further extensive testing is needed, the new modification appears to be a promising step toward a more reliable description of noncanonical DNA motifs and provides the best performance for Z-DNA molecules among current AMBER force fields.
- MeSH
- B-DNA chemie MeSH
- konformace nukleové kyseliny MeSH
- simulace molekulární dynamiky MeSH
- Z-DNA * MeSH
- Publikační typ
- časopisecké články MeSH
We study the folding of the designed hairpin chignolin, using simulations with four different force fields. Interestingly, we find a misfolded, out-of-register, structure comprising 20-50% of the ordered structures with three force fields, but not with a fourth. A defining feature of the misfold is that Gly-7 adopts a β(PR) conformation rather than α(L). By reweighting, we show that differences between the force fields can mostly be attributed to differences in glycine properties. Benchmarking against NMR data suggests that the preference for β(PR) is not a force-field artifact. For chignolin, we show that including the misfold in the ensemble results in back-recalculated NMR observables in slightly better agreement with experiment than parameters calculated from a folded ensemble only. For comparison, we show by NMR and circular dichroism spectroscopy that the G7K mutant of chignolin, in which formation of this misfold is impossible, is well folded with stability similar to the wild-type and does not populate the misfolded state in simulation. Our results highlight the complexity of interpreting NMR data for small, weakly structured, peptides in solution, as well as the importance of accurate glycine parameters in force fields, for a correct description of turn structures.
Hypothesis of coherent vibration states in biological systems based on nonlinear interaction between longitudinal elastic and electric polarization fields with metabolic energy supply was formulated by Frohlich. Conditions for excitation of coherent states and generation of electromagnetic fields are satisfied in microtubules which form electrical polar structures. Numerical models are used for analysis of Frohlich's vibration states in cells. Reduction of activity and of energy production in mitochondria, and disintegration of cytoskeleton structures by phosphorylation on the pathway of cancer trasformation can diminish excitation of the Frohlich's vibration states and of the generated electromagnetic field, which results in disturbances of the interaction forces between cells. Interaction forces between cancer cells may be smaller than interaction forces between healthy cells and cancer cells as follows from numerical models. Mechanism of malignity, i.e. local invasion, detachment of cancer cells, and metastasis, is assumed to depend on the electromagnetic field.
- MeSH
- biofyzika metody MeSH
- biologické modely MeSH
- buňky 3T3 MeSH
- cytoskelet metabolismus MeSH
- elektromagnetická pole MeSH
- elektromagnetické jevy MeSH
- lidé MeSH
- mikroskopie atomárních sil MeSH
- mikrotubuly metabolismus MeSH
- mitochondrie metabolismus MeSH
- myši MeSH
- nádory metabolismus MeSH
- pružnost MeSH
- Saccharomyces cerevisiae metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
Enzymatic activity (denitrification) of Paracoccus denitrificans was estimated electrochemically by reduction of duroquinone (DQ). Graphite electrodes covered with whole bacterial cells behind a dialysis membrane were used for measurement. P. denitrificans reduce nitrate and/or nitrite under anaerobic conditions to nitrogen gas. DQ acts as an electron mediator. After donation of the electrons to the respiratory system of the bacteria, produced DQ is reduced to durohydroquinone on the electrode surface electrocatalytically. P. denitrificans were exposed to low-frequency magnetic field (10 mT, 50 Hz) for 24 min. In comparison with the control samples, the reduction peak of I-E curves that represent denitrification activity of the cells decreased significantly after magnetic field exposure. The decrease of the peak current was about 20%. The CFU-colony forming units-method was used to estimate the number of surviving bacteria. After 24 min exposure of 10 mT magnetic field P. denitrificans culture on electrode indicates 21% bacterial death.
Determination of RNA structural-dynamic properties is challenging for experimental methods. Thus, atomistic molecular dynamics (MD) simulations represent a helpful technique complementary to experiments. However, contemporary MD methods still suffer from limitations of force fields (ffs), including imbalances in the nonbonded ff terms. We have recently demonstrated that some improvement of state-of-the-art AMBER RNA ff can be achieved by adding a new term for H-bonding called gHBfix, which increases tuning flexibility and reduces risk of side-effects. Still, the first gHBfix version did not fully correct simulations of short RNA tetranucleotides (TNs). TNs are key benchmark systems due to availability of unique NMR data, although giving too much weight on improving TN simulations can easily lead to overfitting to A-form RNA. Here we combine the gHBfix version with another term called tHBfix, which separately treats H-bond interactions formed by terminal nucleotides. This allows to refine simulations of RNA TNs without affecting simulations of other RNAs. The approach is in line with adopted strategy of current RNA ffs, where the terminal nucleotides possess different parameters for terminal atoms than the internal nucleotides. Combination of gHBfix with tHBfix significantly improves the behavior of RNA TNs during well-converged enhanced-sampling simulations using replica exchange with solute tempering. TNs mostly populate canonical A-form like states while spurious intercalated structures are largely suppressed. Still, simulations of r(AAAA) and r(UUUU) TNs show some residual discrepancies with primary NMR data which suggests that future tuning of some other ff terms might be useful. Nevertheless, the tHBfix has a clear potential to improve modeling of key biochemical processes, where interactions of RNA single stranded ends are involved.
- MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- nukleotidy chemie MeSH
- RNA chemie MeSH
- simulace molekulární dynamiky normy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The coarse-grained Martini force field is widely used in biomolecular simulations. Here we present the refined model, Martini 3 ( http://cgmartini.nl ), with an improved interaction balance, new bead types and expanded ability to include specific interactions representing, for example, hydrogen bonding and electronic polarizability. The updated model allows more accurate predictions of molecular packing and interactions in general, which is exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.
