Transcription-induced active forces suppress chromatin motion.

The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some experiments have shown that the motility of individual loci in human interphase chromosome decreases during transcription and increases upon inhibiting transcription. This is a counterintuitive finding because it is thought that the active mechanical force (F) on the order of ten piconewtons, generated by RNA polymerase II (RNAPII) that is presumably transmitted to the gene-rich region of the chromatin, would render it more open, thus enhancing the mobility. We developed a minimal active copolymer model for interphase chromosomes to investigate how F affects the dynamical properties of chromatin. The movements of the loci in the gene-rich region are suppressed in an intermediate range of F and are enhanced at small F values, which has also been observed in experiments. In the intermediate F, the bond length between consecutive loci increases, becoming commensurate with the distance at the minimum of the attractive interaction between nonbonded loci. This results in a transient disorder-to-order transition, leading to a decreased mobility during transcription. Strikingly, the F-dependent change in the locus dynamics preserves the organization of the chromosome at [Formula: see text]. Transient ordering of the loci, which is not found in the polymers with random epigenetic profiles, in the gene-rich region might be a plausible mechanism for nucleating a dynamic network involving transcription factors, RNAPII, and chromatin.

Entropic contribution of ACE2 glycans to RBD binding.

The spike protein of the SARS-CoV-2 virus (the causative agent of COVID-19) recognizes the host cell by binding to the peptidase domain (PD) of the extracellular receptor angiotensin-converting enzyme 2 (ACE2). A variety of carbohydrates could be attached to the six asparagines in the PD, resulting in a heterogeneous population of ACE2 glycoforms. Experiments have shown that the binding affinity of glycosylated and deglycosylated ACE2 to the virus is virtually identical. In most cases, the reduction in glycan size correlates with stronger binding, which suggests that volume exclusion, and hence entropic forces, determine the binding affinity. Here, we quantitatively test the entropy-based hypothesis by developing a lattice model for the complex between ACE2 and the SARS-CoV-2 spike protein receptor-binding domain (RBD). Glycans are treated as branched polymers with only volume exclusion, which we justify using all-atom molecular dynamics simulations in explicit water. We show that the experimentally measured changes in the ACE2-RBD dissociation constants for a variety of engineered ACE2 glycoforms are in reasonable agreement with our theory, thus supporting our hypothesis. However, a quantitative recovery of all the experimental data could require weak attractive interactions.

Quantifying the Molecular Polarization Response of Liquid Water Interfaces at Heterogeneously Charged Surfaces.

The hydration shells of proteins mediate interactions, such as small molecule binding, that are vital to their biological function or in some cases their dysfunction. However, even when the structure of a protein is known, the properties of its hydration environment cannot be easily predicted due to the complex interplay between protein surface heterogeneity and the collective structure of water's hydrogen bonding network. This manuscript presents a theoretical study of the influence of surface charge heterogeneity on the polarization response of the liquid water interface. We focus our attention on classical point charge models of water, where the polarization response is limited to molecular reorientation. We introduce a new computational method for analyzing simulation data that is capable of quantifying water's collective polarization response and determining the effective surface charge distribution of hydrated surfaces over atomistic length scales. To illustrate the utility of this method, we present the results of molecular dynamics simulations of liquid water in contact with a heterogeneous model surface and the CheY protein.

Water Dynamics Around Proteins: T- and R-States of Hemoglobin and Melittin.

The water dynamics, as characterized by the local hydrophobicity (LH), is investigated for tetrameric hemoglobin (Hb) and dimeric melittin. For the T0 to R0 transition in Hb, it is found that LH provides additional molecular-level insight into the Perutz mechanism, i.e., the breaking and formation of salt bridges at the α1/ß2 and α2/ß1 interface is accompanied by changes in LH. For Hb in cubic water boxes with 90 and 120 Å edge length it is observed that following a decrease in LH as a consequence of reduced water density or change of water orientation at the protein/water interface the α/ß interfaces are destabilized; this is a hallmark of the Perutz stereochemical model for the T to R transition in Hb. The present work thus provides a dynamical view of the classical structural model relevant to the molecular foundations of Hb function. For dimeric melittin, earlier results by Cheng and Rossky [ Nature 1998, 392, 696-699] are confirmed and interpreted on the basis of LH from simulations in which the protein structure is frozen. For the flexible melittin dimer, the changes in the local hydration can be as much as 30% greater than for the rigid dimer, reflecting the fact that protein and water dynamics are coupled.

Water's Interfacial Hydrogen Bonding Structure Reveals the Effective Strength of Surface-Water Interactions.

The interactions of a hydrophilic surface with water can significantly influence the characteristics of the liquid water interface. In this manuscript, we explore this influence by studying the molecular structure of liquid water at a disordered surface with tunable surface-water interactions. We combine all-atom molecular dynamics simulations with a mean field model of interfacial hydrogen bonding to analyze the effect of surface-water interactions on the structural and energetic properties of the liquid water interface. We find that the molecular structure of water at a weakly interacting (i.e., hydrophobic) surface is resistant to change unless the strength of surface-water interactions is above a certain threshold. We find that below this threshold water's interfacial structure is homogeneous and insensitive to the details of the disordered surface, however, above this threshold water's interfacial structure is heterogeneous. Despite this heterogeneity, we demonstrate that the equilibrium distribution of molecular orientations can be used to quantify the energetic component of the surface-water interactions that contribute specifically to modifying the interfacial hydrogen bonding network. We identify this specific energetic component as a new measure of hydrophilicity, which we refer to as the intrinsic hydropathy.

Three-Body Hydrogen Bond Defects Contribute Significantly to the Dielectric Properties of the Liquid Water-Vapor Interface.

We present a simple model of aqueous interfacial molecular structure, and we use this model to isolate the effects of hydrogen bonding on the dielectric properties of the liquid water-vapor interface. We show that water's interfacial molecular structure can be understood by considering the orientational preferences of a single molecule immersed in the environment of the average interfacial density field. We illustrate that depth-dependent orientational anisotropy is determined by the geometric constraints of hydrogen bonding, and we show that the primary features of atomistic simulation data can be reproduced by assuming an idealized, perfectly tetrahedral hydrogen bonding geometry. We demonstrate that nonideal hydrogen bond geometries are required to account for variations in the orientational polarization and polarizability of the interface. Finally, we highlight that these properties contain significant contributions from a specific type of geometrically distorted three-body hydrogen bond defect that is preferentially stabilized at the interface.

Characterizing Hydration Properties Based on the Orientational Structure of Interfacial Water Molecules.

In this work, we present a general computational method for characterizing the molecular structure of liquid water interfaces as sampled from atomistic simulations. With this method, the interfacial structure is quantified based on the statistical analysis of the orientational configurations of interfacial water molecules. The method can be applied to generate position dependent maps of the hydration properties of heterogeneous surfaces. We present an application to the characterization of surface hydrophobicity, which we use to analyze simulations of a hydrated protein. We demonstrate that this approach is capable of revealing microscopic details of the collective dynamics of a protein hydration shell.