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On the force field optimisation of [Formula: see text]-lactam cores using the force field Toolkit.

ABSTRACT: When employing molecular dynamics (MD) simulations for computer-aided drug design, the quality of the used force fields is highly important. Here we present reparametrisations of the force fields for the core molecules from 9 different [Formula: see text]-lactam classes, for which we utilized the force field Toolkit and Gaussian calculations. We focus on the parametrisation of the dihedral angles, with the goal of reproducing the optimised quantum geometry in MD simulations. Parameters taken from CGenFF turn out to be a good initial guess for the multiplicity of each dihedral angle, but the key to a successful parametrisation is found to lie in the phase shifts. Based on the optimised quantum geometry, we come up with a strategy for predicting the phase shifts prior to the dihedral potential fitting. This allows us to successfully parameterise 8 out of the 11 molecules studied here, while the remaining 3 molecules can also be parameterised with small adjustments. Our work highlights the importance of predicting the dihedral phase shifts in the ligand parametrisation protocol, and provides a simple yet valuable strategy for improving the process of parameterising force fields of drug-like molecules.

SUBMITTER: Wu Q

PROVIDER: S-EPMC9399072 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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On the force field optimisation of β-lactam cores using the force field Toolkit.

Wu Qiyang Q Huang Tianyang T Xia Songyan S Otto Frank F Lee Tzong-Yi TY Huang Hsien-Da HD Chiang Ying-Chih YC

Journal of computer-aided molecular design 20220711 7

When employing molecular dynamics (MD) simulations for computer-aided drug design, the quality of the used force fields is highly important. Here we present reparametrisations of the force fields for the core molecules from 9 different β-lactam classes, for which we utilized the force field Toolkit and Gaussian calculations. We focus on the parametrisation of the dihedral angles, with the goal of reproducing the optimised quantum geometry in MD simulations. Parameters taken from CGenFF turn out ...[more]

PMID: 35819650

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Project description:The experimental value for the isospin amplitude [Formula: see text] in [Formula: see text] decays has been successfully explained within the standard model (SM), both within the large [Formula: see text] approach to QCD and by QCD lattice calculations. On the other hand within the large [Formula: see text] approach the value of [Formula: see text] is by at least [Formula: see text] below the data. While this deficit could be the result of theoretical uncertainties in this approach and could be removed by future precise QCD lattice calculations, it cannot be excluded that the missing piece in [Formula: see text] comes from new physics (NP). We demonstrate that this deficit can be significantly softened by tree-level FCNC transitions mediated by a heavy colourless [Formula: see text] gauge boson with a flavour-violating left-handed coupling [Formula: see text] and an approximately universal flavour diagonal right-handed coupling [Formula: see text] to the quarks. The approximate flavour universality of the latter coupling assures negligible NP contributions to [Formula: see text]. This property, together with the breakdown of the GIM mechanisms at tree level, allows one to enhance significantly the contribution of the leading QCD-penguin operator [Formula: see text] to [Formula: see text]. A large fraction of the missing piece in the [Formula: see text] rule can be explained in this manner for [Formula: see text] in the reach of the LHC, while satisfying the constraints from [Formula: see text], [Formula: see text], [Formula: see text], LEP-II and the LHC. The presence of a small right-handed flavour-violating coupling [Formula: see text] and of enhanced matrix elements of [Formula: see text] left-right operators allows one to satisfy simultaneously the constraints from [Formula: see text] and [Formula: see text], although this requires some fine-tuning. We identify the quartic correlation between [Formula: see text] contributions to [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. The tests of this proposal will require much improved evaluations of [Formula: see text] and [Formula: see text] within the SM, of [Formula: see text] as well as precise tree-level determinations of [Formula: see text] and [Formula: see text]. We present correlations between [Formula: see text], [Formula: see text] and [Formula: see text] with and without the [Formula: see text] rule constraint and generalise the whole analysis to [Formula: see text] with colour ([Formula: see text]) and [Formula: see text] with FCNC couplings. In the latter case no improvement on [Formula: see text] can be achieved without destroying the agreement of the SM with the data on [Formula: see text]. Moreover, this scenario is very tightly constrained by [Formula: see text]. On the other hand, in the context of the [Formula: see text] rule [Formula: see text] is even more effective than [Formula: see text]: it provides the missing piece in [Formula: see text] for [Formula: see text]-[Formula: see text].

Project description:Purpose[Formula: see text] mapping is a powerful tool for studying osteoarthritis (OA) changes and bilateral imaging may be useful in investigating the role of between-knee asymmetry in OA onset and progression. The quantitative double-echo in steady-state (qDESS) can provide fast simultaneous bilateral knee [Formula: see text] and high-resolution morphometry for cartilage and meniscus. The qDESS uses an analytical signal model to compute [Formula: see text] relaxometry maps, which require knowledge of the flip angle (FA). In the presence of [Formula: see text] inhomogeneities, inconsistencies between the nominal and actual FA can affect the accuracy of [Formula: see text] measurements. We propose a pixel-wise [Formula: see text] correction method for qDESS [Formula: see text] mapping exploiting an auxiliary [Formula: see text] map to compute the actual FA used in the model.MethodsThe technique was validated in a phantom and in vivo with simultaneous bilateral knee imaging. [Formula: see text] measurements of femoral cartilage (FC) of both knees of six healthy participants were repeated longitudinally to investigate the association between [Formula: see text] variation and [Formula: see text].ResultsThe results showed that applying the [Formula: see text] correction mitigated [Formula: see text] variations that were driven by [Formula: see text] inhomogeneities. Specifically, [Formula: see text] left-right symmetry increased following the [Formula: see text] correction ([Formula: see text] = 0.74 > [Formula: see text] = 0.69). Without the [Formula: see text] correction, [Formula: see text] values showed a linear dependence with [Formula: see text]. The linear coefficient decreased using the [Formula: see text] correction (from 24.3 ± 1.6 ms to 4.1 ± 1.8) and the correlation was not statistically significant after the application of the Bonferroni correction (p value > 0.01).ConclusionThe study showed that [Formula: see text] correction could mitigate variations driven by the sensitivity of the qDESS [Formula: see text] mapping method to [Formula: see text], therefore, increasing the sensitivity to detect real biological changes. The proposed method may improve the robustness of bilateral qDESS [Formula: see text] mapping, allowing for an accurate and more efficient evaluation of OA pathways and pathophysiology through longitudinal and cross-sectional studies.

Project description:The Josephson effect in point contacts between an "ordinary" superconductor [Formula: see text]In[Formula: see text] ([Formula: see text]) and single crystals of the Fe-based superconductor Ba[Formula: see text]K[Formula: see text](FeAs)[Formula: see text] ([Formula: see text]), was investigated. In order to shed light on the order parameter symmetry of Ba[Formula: see text]K[Formula: see text](FeAs)[Formula: see text], the dependence of the Josephson supercurrent [Formula: see text] on the temperature and on [Formula: see text] with [Formula: see text] was studied. The dependencies of the critical current on temperature [Formula: see text] and of the amplitudes of the first current steps of the current-voltage characteristic [Formula: see text] [Formula: see text] on the power of microwave radiation with frequency [Formula: see text] were measured. It is shown that the dependencies [Formula: see text] are close to the well-known Ambegaokar-Baratoff (AB) dependence for tunnel contacts between "ordinary" superconductors and to the dependence calculated by Burmistrova et al. (Phys Rev B 91, 214501 (2015)) for microshorts between an "ordinary" superconductor and a two-band superconductor with [Formula: see text] order parameter symmetry at certain values of the transparency of boundaries and thickness of the transition layer. It is found that the dependencies [Formula: see text] cannot be approximated within the resistively shunted model using the normalized microwave frequencies [Formula: see text] with characteristic voltages [Formula: see text], [Formula: see text]-normal resistance of the contact) found from the low-voltage parts of the current-voltage characteristics. The reasons for this failure are discussed and a method is proposed for accurately determining the value of [Formula: see text], which takes into account all the features of the point contact affecting the period of the dependence [Formula: see text]. An analysis of the [Formula: see text] and [Formula: see text] dependencies shows that the superconducting current of the Josephson contacts under investigation is proportional to the [Formula: see text] of the phase difference [Formula: see text], [Formula: see text]. The implications of these results on the symmetry of the order parameter are also discussed.

Project description:Although mechanically interlocked molecules (MIMs) display unique properties and functions associated with their intricate connectivity, limited assembly strategies are available for their synthesis. Herein, we presented a synergistic assembly strategy based on coordination and noncovalent interactions (π-π stacking and CH⋯π interactions) to selectively synthesize molecular closed three-link chains ([Formula: see text] links), highly entangled figure-eight knots ([Formula: see text] knots), trefoil knot ([Formula: see text] knot), and Borromean ring ([Formula: see text] link). [Formula: see text] links can be created by the strategic assembly of nonlinear multicurved ligands incorporating a furan or phenyl group with the long binuclear half-sandwich organometallic Cp*RhIII (Cp* = η5-pentamethylcyclopentadienyl) clip. However, utilizing much shorter binuclear Cp*RhIII units for union with the 2,6-naphthyl-containing ligand led to a [Formula: see text] knot because of the increased π-π stacking interactions between four consecutive stacked layers and CH⋯π interactions. Weakening such π-π stacking interactions resulted in a [Formula: see text] knot. The universality of this synergistic assembly strategy for building [Formula: see text] knots was verified by utilizing a 1,5-naphthyl-containing ligand. Quantitative conversion between the [Formula: see text] knot and the simple macrocycle species was accomplished by adjusting the concentrations monitored by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Furthermore, increasing the stiff π-conjugated area of the binuclear unit afforded molecular Borromean ring, and this topology is a topological isomer of the [Formula: see text] link. These artificial metalla-links and metalla-knots were confirmed by single-crystal X-ray diffraction, NMR and ESI-MS. The results offer a potent strategy for building higher-order MIMs and emphasize the critical role that noncovalent interactions play in creating sophisticated topologies.

Dataset Information

On the force field optimisation of [Formula: see text]-lactam cores using the force field Toolkit.

Publications

On the force field optimisation of β-lactam cores using the force field Toolkit.

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