End-to-end attraction of duplex DNA

Recent experiments [Nakata, M. et al., End-to-end stacking and liquid crystal condensation of 6 to 20 basepair DNA duplexes. Science 2007; 318:1276–1279] have demonstrated spontaneous end-to-end association of short duplex DNA fragments into long rod-like structures. By means of extensive all-atom molecular dynamic simulations, we characterized end-to-end interactions of duplex DNA, quantitatively describing the forces, free energy and kinetics of the end-to-end association process. We found short DNA duplexes to spontaneously aggregate end-to-end when axially aligned in a small volume of monovalent electrolyte. It was observed that electrostatic repulsion of 5′-phosphoryl groups promoted the formation of aggregates in a conformation similar to the B-form DNA double helix. Application of an external force revealed that rupture of the end-to-end assembly occurs by the shearing of the terminal base pairs. The standard binding free energy and the kinetic rates of end-to-end association and dissociation processes were estimated using two complementary methods: umbrella sampling simulations of two DNA fragments and direct observation of the aggregation process in a system containing 458 DNA fragments. We found the end-to-end force to be short range, attractive, hydrophobic and only weakly dependent on the ion concentration. The relation between the stacking free energy and end-to-end attraction is discussed as well as possible roles of the end-to-end interaction in biological and nanotechnological systems

Contact of Single Asperities with Varying Adhesion: Comparing Continuum Mechanics to Atomistic Simulations

Atomistic simulations are used to test the equations of continuum contact mechanics in nanometer scale contacts. Nominally spherical tips, made by bending crystals or cutting crystalline or amorphous solids, are pressed into a flat, elastic substrate. The normal displacement, contact radius, stress distribution, friction and lateral stiffness are examined as a function of load and adhesion. The atomic scale roughness present on any tip made of discrete atoms is shown to have profound effects on the results. Contact areas, local stresses, and the work of adhesion change by factors of two to four, and the friction and lateral stiffness vary by orders of magnitude. The microscopic factors responsible for these changes are discussed. The results are also used to test methods for analyzing experimental data with continuum theory to determine information, such as contact area, that can not be measured directly in nanometer scale contacts. Even when the data appear to be fit by continuum theory, extracted quantities can differ substantially from their true values

Contact and Friction of Nano-Asperities: Effects of Adsorbed Monolayers

Molecular dynamics simulations are used to study contact between a rigid, nonadhesive, spherical tip with radius of order 30nm and a flat elastic substrate covered with a fluid monolayer of adsorbed chain molecules. Previous studies of bare surfaces showed that the atomic scale deviations from a sphere that are present on any tip constructed from discrete atoms lead to significant deviations from continuum theory and dramatic variability in friction forces. Introducing an adsorbed monolayer leads to larger deviations from continuum theory, but decreases the variations between tips with different atomic structure. Although the film is fluid, it remains in the contact and behaves qualitatively like a thin elastic coating except for certain tips at high loads. Measures of the contact area based on the moments or outer limits of the pressure distribution and on counting contacting atoms are compared. The number of tip atoms making contact in a time interval grows as a power of the interval when the film is present and logarithmically with the interval for bare surfaces. Friction is measured by displacing the tip at a constant velocity or pulling the tip with a spring. Both static and kinetic friction rise linearly with load at small loads. Transitions in the state of the film lead to nonlinear behavior at large loads. The friction is less clearly correlated with contact area than load.Comment: RevTex4, 17 pages, 13 figure

Field-dependent dehydration and optimal ionic escape paths for C2N membranes

Most analytic theories describing electrostatically-driven ion transport through water-filled nanopores assume that the corresponding permeation barriers are bias-independent. While this assumption may hold for sufficiently wide pores under infinitely small bias, transport through sub-nm pores under finite bias is difficult to interpret analytically. Given recent advances in sub-nm pore fabrication and the rapid progress in detailed computer simulations, it is important to identify and understand the specific field-induced phenomena arising during ion transport. Here we consider an atomistic model of electrostatically-driven ion permeation through subnanoporous C2N membranes. We analyse probability distributions of ionic escape trajectories and show that the optimal escape path switches between two different configurations, depending on bias magnitude. We identify two distinct mechanisms contributing to field-induced changes in transport-opposing barriers: a weak one arising from field-induced ion dehydration and a strong one due to the field-induced asymmetry of the hydration shells. The simulated current-voltage characteristics are compared with the solution of the 1D Nernst-Planck model. Finally, we show that the deviation of simulated currents from analytic estimates for large fields is consistent with the field-induced barriers and the observed changes in the optimal ion escape path

In silico Antibody Mutagenesis for Optimizing its Binding to the Spike Protein of SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2\u27s spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to in silico investigate the molecular mechanism of mAb\u27s binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated in silico protocol for quickly identifying possible mutations in a mAb (e.g.~CB6) to enhance its binding affinity with Spro for the design of more efficacious therapeutic mAbs.</p

In Silico Exploration of Molecular Mechanism and Potency Ranking of Clinically Oriented Drugs for Inhibiting SARS-CoV-2’s Main Protease

Currently, the new coronavirus disease 2019 (COVID-19) is a global pandemic without any well calibrated treatment. To inactivate the SARS-CoV-2 virus that causes COVID-19, the main protease (Mpro) that performs key biological functions in the virus has been the focus of extensive studies. With the fast-response experimental efforts, the crystal structures of Mpro of the SARS-CoV-2 virus have just become available recently. Herein, we theoretically investigated the binding mechanism between the Mpro\u27s pocket and various marketed drug molecules being tested in clinics to fight COVID-19 that show promising outcomes. Combining all existing experiment results with our computational ones, we revealed an important ligand-binding mechanism for the Mpro that the binding stability of a ligand inside the Mpro pocket can be significantly improved if the partial ligand occupies the so-called "anchor" site of the Mpro. Along with the high-potent drugs/molecules (such as nelfinavir and curcumin) revealed in this study, the newly discovered binding mechanism paves the way for further optimizations and designs of Mpro\u27s inhibitors with a high binding affinity. </p

In Silico Exploration of Efficacious Inhibitors for SARS-CoV-2’s Papain-like Protease

We applied the flexible docking method to rank-order all FDA-approved drugs as inhibitors for the papain-like protease (PLpro) of SRAS-CoV-2. We also evaluated these results using molecular dynamics (MD) simulations. From MD simulations, we unveiled the molecular mechanism for a known inhibitor rac5c\u27s binding with PLpro. <br /