Accurate Evaluation of Charge Asymmetry in Aqueous Solvation

Charge hydration asymmetry (CHA)--a characteristic dependence of hydration free energy on the sign of the solute charge--quantifies the asymmetric response of water to electric field at microscopic level. Accurate estimates of CHA are critical for understanding hydration effects ubiquitous in chemistry and biology. However, measuring hydration energies of charged species is fraught with significant difficulties, which lead to unacceptably large (up to 300%) variation in the available estimates of the CHA effect. We circumvent these difficulties by developing a framework which allows us to extract and accurately estimate the intrinsic propensity of water to exhibit CHA from accurate experimental hydration free energies of neutral polar molecules. Specifically, from a set of 504 small molecules we identify two pairs that are analogous, with respect to CHA, to the K+/F- pair--a classical probe for the effect. We use these "CHA-conjugate" molecule pairs to quantify the intrinsic charge-asymmetric response of water to the microscopic charge perturbations: the asymmetry of the response is strong, ~50% of the average hydration free energy of these molecules. The ability of widely used classical water models to predict hydration energies of small molecules correlates with their ability to predict CHA

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Abstract Background Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of three-dimensional (3D) chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult. Results We have developed a coarse-grained dynamical model of D. melanogaster nuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD–NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. The simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development. Predicted positioning of all LADs at the NE is highly dynamic—the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome, which also has the same strong effect on the predicted positioning of individual TADs -- higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD–TAD interactions compared to the lamin depleted nuclei, where a small (0.5 kT) increase of cross-type TAD–TAD interactions doubles the chromatin density in the central nucleus region. Conclusions A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD–NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD–TAD interactions

Introducing Charge Hydration Asymmetry into the Generalized Born Model

The effect of charge hydration asymmetry (CHA)non-invariance of solvation free energy upon solute charge inversionis missing from the standard linear response continuum electrostatics. The proposed charge hydration asymmetric–generalized Born (CHA–GB) approximation introduces this effect into the popular generalized Born (GB) model. The CHA is added to the GB equation via an analytical correction that quantifies the specific propensity of CHA of a given water model; the latter is determined by the charge distribution within the water model. Significant variations in CHA seen in explicit water (TIP3P, TIP4P-Ew, and TIP5P-E) free energy calculations on charge-inverted “molecular bracelets” are closely reproduced by CHA–GB, with the accuracy similar to models such as SEA and 3D-RISM that go beyond the linear response. Compared against reference explicit (TIP3P) electrostatic solvation free energies, CHA–GB shows about a 40% improvement in accuracy over the canonical GB, tested on a diverse set of 248 rigid small neutral molecules (root mean square error, rmse = 0.88 kcal/mol for CHA–GB vs 1.24 kcal/mol for GB) and 48 conformations of amino acid analogs (rmse = 0.81 kcal/mol vs 1.26 kcal/mol). CHA–GB employs a novel definition of the dielectric boundary that does not subsume the CHA effects into the intrinsic atomic radii. The strategy leads to finding a new set of intrinsic atomic radii optimized for CHA–GB; these radii show physically meaningful variation with the atom type, in contrast to the radii set optimized for GB. Compared to several popular radii sets used with the original GB model, the new radii set shows better transferability between different classes of molecules

Charge Hydration Asymmetry: The Basic Principle and How to Use It to Test and Improve Water Models

Charge hydration asymmetry (CHA) manifests itself in the experimentally observed strong dependence of free energy of ion hydration on the sign of the ion charge. This asymmetry is not consistently accounted for by popular models of solvation; its magnitude varies greatly between the models. While it is clear that CHA is somehow related to charge distribution within a water molecule, the exact nature of this relationship is unknown. We propose a simple, yet general and rigorous criterion that relates rotational and charge inversion properties of a water molecule’s charge distribution with its ability to cause CHA. We show which electric multipole components of a water molecule are key to explain its ability for asymmetric charge hydration. We then test several popular water models and explain why specific models show none, little, or strong CHA in simulations. We use the gained insight to derive an analogue of the Born equation that includes the missing physics necessary to account for CHA and does not rely on redefining the continuum dielectric boundary. The proposed formula is as simple as the original, does not contain any fitting parameters, and predicts hydration free energies and entropies of spherical cations and anions within experimental uncertainty. Our findings suggest that the gap between the practical continuum electrostatics framework and the more fundamental explicit solvent treatment may be reduced considerably by explicitly introducing CHA into the existing continuum framework