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The molecular dynamics (MD) computer simulation technique is powerful for the investigation of conformational equilibrium properties of biomolecules. In particular, free energy surfaces of the torsion angles (those degrees of freedom from which the geometry mostly depends) allow one to access conformational states, as well as kinetic information, i.e., if the transitions between conformational states occur by simple jumps between wells or if conformational regions close to these states also are populated. The information obtained from MD simulations may depend substantially on the force field employed, and thus, a validation procedure is essential. NMR relaxation data are expected to be highly sensitive to the details of the torsional free energy surface. As a case-study, we consider the disaccharide α-l-Rhap-(1 → 2)-α-l-Rhap-OMe that features only two important torsion angles, ϕ and ψ, which define the interglycosidic orientation of the sugar residues relative to each other, governed mainly by the exo-anomeric effect and steric interactions, respectively. In water, a ψ− state is preferred, whereas in DMSO, it is a ψ+ state, suggesting inherent flexibility at the torsion angle. MD simulations indicated that bistable potentials describe the conformational region well. To test whether a unimodal distribution suffices or if a bimodal distribution better represents molecular conformational preferences, we performed an alchemical morphing of the torsional free energy surface and computed T1, T2, and NOE13C NMR relaxation data that were compared to experimental data. All three NMR observables are substantially affected by the morphing procedure, and the results strongly support a bimodal Boltzmann equilibrium density with a major and a minor conformational state bisected at ψ ≈ 0°, in accord with MD simulations in an explicit solvent. [ABSTRACT FROM AUTHOR]

In Paper I [Polimeno et al., J. Chem. Phys. 150, 184107 (2019)], we proposed a general approach for interpreting relaxation properties of a macromolecule in solution, derived from an atomistic description. A simple scheme (the semiflexible Brownian, SFB, model) has been defined for the case of limited internal flexibility, but retaining full coupling with external degrees of freedom, inclusion of all of the momenta, and dissipation. Here we discuss the application of the SFB model to the practical evaluation of orientation spectral densities, based on two complementary computational treatments. [ABSTRACT FROM AUTHOR]

A framework for the stochastic description of relaxation processes in flexible macromolecules, including dissipative effects, is introduced from an atomistic point of view. Projection-operator techniques are employed to obtain multidimensional Fokker-Planck operators governing the relaxation of internal coordinates and global degrees of freedom and depending upon parameters fully recoverable from classic force fields (energetics) and continuum models (friction tensors). A hierarchy of approaches of different complexity is proposed in this unified context, aimed primarily at the interpretation of magnetic resonance relaxation experiments. In particular, a model based on a harmonic internal Hamiltonian is discussed as a test case. [ABSTRACT FROM AUTHOR]

The mechanism of force-fitting is investigated in order to elucidate the slowly relaxing local structure (SRLS) version and it is shown that the model-free approach is a very simplified version for analyzing spin relaxation data in proteins. The analysis has shown that SRLS spectral density matches the integrity of currently available experimental data.

Mechanism of molecular relaxation in liquids using LSCM is described. This methodology could be an efficient tool to interpret spectroscopic measurements.

We estimate the kinetic constants of a series of archetypal SN2 reactions, i.e., the nucleophilic substitutions of halides in halomethane. A parameter free, multiscale approach recently developed [Campeggio et al., Phys. Chem. Chem. Phys., 2020, 22, 3455] is employed. The protocol relies on quantum mechanical calculations for the description of the energy profile along the intrinsic reaction coordinate, which is then mapped onto a reaction coordinate conveniently built for the reactive process. A Kramers–Klein equation is used to describe the stochastic time evolution of the reaction coordinate and its velocity; friction is parameterized using a hydrodynamic model and Kramers theory is used to derive the rate constant of the reaction. The method is here applied to six SN2 reactions in water at 295.15 K, which differ in the nucleophile and the leaving group. The computed reaction rates are in good agreement with the experimental data and correlate well with the trends observed for the activation energies. [ABSTRACT FROM AUTHOR]

We propose an approach to the evaluation of kinetic rates of elementary chemical reactions within Kramers' theory based on the definition of the reaction coordinate as a linear combination of natural, pseudo Z-matrix, internal coordinates of the system. The element of novelty is the possibility to evaluate the friction along the reaction coordinate, within a hydrodynamic framework developed recently [J. Campeggio et al., J. Comput. Chem. 2019, 40, 679–705]. This, in turn, allows to keep into account barrier recrossing, i.e. the transmission coefficient that is employed in correcting transition state theory evaluations. To test the capabilities and the flaws of the approach we use as case studies two archetypal SN2 reactions. First, we consider to the standard substitution of chloride ion to bromomethane. The rate constant at 295.15 K is evaluated to k/c = 2.7 × 10−6 s−1 (with c = 1 M), which compares well to the experimental value of 3.3 × 10−6 s−1 [R. H. Bathgate and E. A. Melwyn-Hughes, J. Chem. Soc 1959, 2642–2648]. Then, the method is applied to the SN2 reaction of methylthiolate to dimethyl disulfide in water. In biology, such an interconversion of thiols and disulfides is an important metabolic topic still not entirely rationalized. The predicted rate constant is k/c = 7.7 × 103 s−1. No experimental data is available for such a reaction, but it is in accord with the fact that the alkyl thiolates to dialkyl disulfides substitutions in water have been found to be fast reactions [S. M. Bachrach, J. M. Hayes, T. Dao and J. L. Mynar, Theor. Chem. Acc. 2002, 107, 266–271]. [ABSTRACT FROM AUTHOR]

Connexins (Cx) are a class of membrane proteins important for auditory function, intercellular signalling and skin biology. Although the presence of concentration of calcium ions is known to work as a trigger for the Cx functionality, the structural changes induced by calcium binding still need to be well elucidated. In this computational study, we have explored the structural effects promoted by Ca2+ on both the wild type (Cx26WT) and on two post-translationally modified Connexin 26 (Cx26): Cx26E42-47γ, which contains two glutamates (E42 and E47) that are γ-carboxylated and Cx26R75m, where a key arginine (R75) is N-monomethylated. These modified amino acids, whose forcefield parameters have been developed in this work, alter Cx26 structure around the Ca2+coordination site. Structural changes were assessed from the analysis of molecular dynamics (MD) simulations. We observed a strict relation between the chemical properties of the post-translational modifications and significantly different responses of Cx26 to Ca2+-binding, while charge-adding modifications have destabilising effects upon calcium coordination, the uncharged ones share the same structural properties of the wild-type counterpart. Overall, these findings suggest the critical role of the electrostatic network flanking the Ca2+ coordination site in maintaining the native tertiary and quaternary structures. [ABSTRACT FROM AUTHOR]

The description of the reorientational dynamics of flexible molecules is a challenging task, in particular when the rates of internal and global motions are comparable. The commonly used simple mode-decoupling models are based on the assumption of statistical independence between these motions. This assumption is not valid when the time scale separation between their rates is small, a situation that was found to arise in oligosaccharides in the context of certain internal motions. To make possible the interpretation of NMR spin relaxation data from such molecules, we developed a comprehensive approach generally applicable to flexible rotators with one internal degree of freedom. This approach integrates a stochastic description of coupled global tumbling and internal torsional motion, quantum chemical calculations of the local potential and the local geometry at the site of the restricted torsion, and hydrodynamics-based calculations of the diffusive properties. The method is applied to the disaccharide β-D-Glcp-(1→6)-α-D-[6-13C]-Manp-OMe dissolved in a DMSO-d6/D2O cryosolvent. The experimental NMR relaxation parameters, associated with the 13CH2 probe residing at the glycosidic linkage, include 13C T1 and T2 and 13C-{1H} nuclear Overhauser enhancement (NOE) as well as longitudinal and transverse dipole-dipole cross-correlated relaxation rates, acquired in the temperature range of 253–293 K. These data are predicted successfully by the new theory with only the H–C–H angle allowed to vary. Previous attempts to fit these data using mode-decoupling models failed. [ABSTRACT FROM AUTHOR]

We present a study of the translational friction coefficients of spherical and ellipsoidal probes in nematic liquid crystalline fluids, based on the numerical treatment of Leslie-Ericksen equations [Q. J. Mech. Appl. Math. 19, 357 (1966); Adv. Liq. Cryst. 4, (1979); Trans. Soc. Rheol. 5, 23 (1961); Adv. Liq. Cryst. 2, 233 (1976)] for incompressible nematic fluids. Simulations of director dynamics in a local environment surrounding the moving probe are presented, and the dependence of translational diffusion on liquid crystal viscoelastic parameters is discussed. The time evolution of the director field is studied in the presence of an orienting magnetic field in two characteristic situations: Directors of motion parallel and perpendicular with respect to the field. In the particular case under investigation, a detailed analysis is given for the case of spherical, prolate, and oblate ellipsoidal probes in rectilinear motion in nematic (4-methoxibenzylidene-4′-n-butylaniline), together with a comparison with other nematogens, namely, 4,4′-dimethoxuazoxy benzene and (4′-n-pentyl-4-cyanobiphenil). A discussion of the general methodology presented in this work is given for the case of colloidal dispersions in nematic liquid crystals, which are considered as model systems of dispersions of particles in host media with anisotropic physical properties. [ABSTRACT FROM AUTHOR]

Electron spin resonance (ESR) measurements are highly informative on the dynamic behavior of molecules, which is of fundamental importance to understand their stability, biological functions and activities, and catalytic action. The wealth of dynamic information which can be extracted from a continuous wave electron spin resonance (cw-ESR) spectrum can be inferred by a basic theoretical approach defined within the stochastic Liouville equation formalism, i.e., the direct inclusion of motional dynamics in the form of stochastic (Fokker-Planck/diffusive) operators in the super Hamiltonian H⁁ governing the time evolution of the system. Modeling requires the characterization of magnetic parameters (e.g., hyperfine and Zeeman tensors) and the calculation of ESR observables in terms of spectral densities. The magnetic observables can be pursued by the employment of density functional theory which is apt, provided that hybrid functionals are employed, for the accurate computation of structural properties of molecular systems. Recently, an ab initio integrated computational approach to the in silico interpretation of cw-ESR spectra of multilabeled systems in isotropic fluids has been discussed. In this work we present the extension to the case of nematic liquid crystalline environments by performing simulations of the ESR spectra of the prototypical nitroxide probe 4-(hexadecanoyloxy)-2,2,6,6-tetramethylpiperidine-1-oxy in isotropic and nematic phases of 5-cyanobiphenyl. We first discuss the basic ingredients of the integrated approach, i.e., (1) determination of geometric and local magnetic parameters by quantum-mechanical calculations, taking into account the solvent and, when needed, the vibrational averaging contributions; (2) numerical solution of a stochastic Liouville equation in the presence of diffusive rotational dynamics, based on (3) parameterization of diffusion rotational tensor provided by a hydrodynamic model. Next we present simulated spectra with minimal resorting to fitting procedures, proving that the combination of sensitive ESR spectroscopy and sophisticated modeling can be highly helpful in providing three-dimensional structural and dynamic information on molecular systems in anisotropic environments. [ABSTRACT FROM AUTHOR]

Dynamics of single molecules in liquids, inspected in the picosecond time scale by means of spectroscopic measurements or molecular-dynamics (MD) simulations, reveals a complex behavior which can be addressed as due to local confinement (cage). This work is devoted to the analysis of cage structures in liquid benzene, obtained from MD simulations. According to a paradigm proposed for previous analysis of atomic and molecular liquids [see, for example, A. Polimeno, G. J. Moro, and J. H. Freed, J. Chem. Phys. 102, 8094 (1995)], the istantaneous cage structure is specified by the frame of axes which identifies the molecular configuration at the closest minimum on the potential-energy landscape. In addition, the modeling of the interaction potential between probe molecule and molecular environment, based on symmetry considerations, and its parametrization from the MD trajectories, allows the estimation of the structural parameters which quantify the strength of molecular confinement. Roto-translational dynamics of probe and related cage with respect to a laboratory frame, dynamics of the probe within the cage (vibrations, librations, re-orientational motions), and the restructuring processes of the cage itself are analyzed in terms of selected time self-correlation functions. A time-scale separation between the processes is established. Moreover, by exploiting the evidence of fast vibrational motions of the probe with respect to the cage center, an orientational effective potential is derived to describe the caging in the time scale longer than ∼0.2 ps. [ABSTRACT FROM AUTHOR]

Simulations of nematic and smectic mesophases based on a dissipative particle dynamics approach are discussed. Mesogenic units are built in the form of standard semirigid bead-spring chains. It is shown that nematic phases can be formed for chains containing at least eight beads, provided that the conservative soft-repulsive potential between nonconnected beads is sufficiently strong. Smectic phases are observed only by modifying the repulsive interaction between the main-chain and terminal beads. The simulations indicate that the smectic-nematic and smectic-isotropic phase transitions take place through the buckling of the smectic layering in the system. [ABSTRACT FROM AUTHOR]

The viscoelastic behavior of a nematic dimer is studied by deuteron ([sup 2]H) nuclear magnetic resonance (NMR) spectroscopy using a cone-and-plate rheometer. From the [sup 2]H NMR spectra, monitored as a function of the shear rate, the orientation of the director relative to the magnetic field is obtained. Analysis of this experiment, using an analytical and a numerical solution of the LeslieEricksen equations, gives detailed information on the viscoelastic properties of the dimer. In particular, the two Leslie viscosities α[sub 2] and α[sub 3] and the three-dimensional director distribution are determined. The analysis reveals that α[sub 2] and α[sub 3] are both positive, that is, the dimer is of the flow-aligning type, and the director is tilted by an angle of about 33° from the magnetic field toward the velocity axis. [ABSTRACT FROM AUTHOR]

The development of a stochastic model for the interpretation of the emission fluorescence of 4-(N,N-dimethylamino)benzonitrile (DMABN) in polar environment is reported. The model allows to estimate the emission fluorescence by numerically solving the diffusion/sink/source equation for the stationary population of excited state.

An ab initio integrated computational approach is applied to evaluate the interpretation of the continuous wave electron spin resonance (CW-ESR) spectra of the double-spin labeled, [3.sub.10]-helical, peptide Fmoc-[(Aib-Aib-TOAC).sub.2]-Aib-OMe dissolved in acetonitrile. It is suggested that combination of sensitive ESR spectroscopy and sophisticated modeling can provide three-dimensional (3D) structural and dynamic information on molecular systems.

NMR spin relaxation of [.sup.2.H] nuclei in [.sup.13.CH2]D groups is a powerful method for studying side-chain motion in proteins. The analysis is typically conducted with the original model-free (MF) approach adapted to methyl dynamics.