Unveiling Nucleosome Dynamics: A Comparative Study Using All-Atom and Coarse-Grained Simulations Enhanced by Principal Component Analysis.

This study investigates nucleosome dynamics using both all-atom and coarse-grained (CG) molecular dynamics simulations, focusing on the SIRAH force field. Simulations are performed for two nucleosomal DNA sequences-ASP and Widom-601-over six microseconds at physiological salt concentrations. Comparative analysis of structural parameters, such as groove widths and base pair geometries, reveals good agreement between atomistic and CG models, though CG simulations exhibit broader conformational sampling and greater breathing motion of DNA ends.

Conformational Dynamics of the Nucleosomal Histone H2B Tails Revealed by Molecular Dynamics Simulations.

Epigenetic modifications of histone N-terminal tails play a critical role in regulating the chromatin structure and biological processes such as transcription and DNA repair. One of the key post-translational modifications (PTMs) is the acetylation of lysine residues on histone tails. Epigenetic modifications are ubiquitous in the development of diseases, such as cancer and neurological disorders.

Sequence Dependence in Nucleosome Dynamics.

The basic packaging unit of eukaryotic chromatin is the nucleosome that contains 145-147 base pair duplex DNA wrapped around an octameric histone protein. While the DNA sequence plays a crucial role in controlling the positioning of the nucleosome, the molecular details behind the interplay between DNA sequence and nucleosome dynamics remain relatively unexplored. This study analyzes this interplay in detail by performing all-atom molecular dynamics simulations of nucleosomes, comparing the human α-satellite palindromic (ASP) and the strong positioning "Widom-601" DNA sequence at time scales of 12 μs.

Molecular Dynamics Simulations of Polyelectrolyte Complexes.

Polyelectrolyte complexes (PECs) are currently of great interest due to their applications toward developing new adaptive materials and their relevance in membraneless organelles. These complexes emerge during phase separation when oppositely charged polymers are mixed in aqueous media. Peptide-based PECs are particularly useful toward developing new drug delivery methods due to their inherent biocompatibility.

Exploration of the Nucleation Pathway for Supramolecular Fibers.

The pathway for supramolecular fiber formation is coupled with the underlying order of the self-assembling molecules. Here, we report on atomistic molecular dynamics simulations to characterize the initial stages of the self-assembly of a model drug amphiphile in an aqueous solution. We perform two-dimensional metadynamics calculations to characterize the assembly space of this model drug amphiphile─Tubustecan, TT1.

PEO--PBD Diblock Copolymers Induce Packing Defects in Lipid/Hybrid Membranes and Improve Insertion Rates of Natively Folded Peptides.

Hybrid membranes assembled from biological lipids and synthetic polymers are a promising scaffold for the reconstitution and utilization of membrane proteins. Recent observations indicate that inclusion of small fractions of polymer in lipid membranes can improve protein folding and function, but the exact structural and physical changes a given polymer sequence imparts on a membrane often remain unclear. Here, we use all-atom molecular dynamics simulations to study the structure of hybrid membranes assembled from DOPC phospholipids and PEO--PBD diblock copolymers.

The Interaction of Supramolecular Anticancer Drug Amphiphiles with Phospholipid Membranes.

The shape of drug delivery vehicles impacts both the circulation time and the effectiveness of the vehicle. Peptide-based drug amphiphiles (DAs) are promising new candidates as drug delivery vehicles that can self-assemble into shapes such as nanofilament and nanotube (diameter ~ 6-10 nm). The number of conjugated drugs affects the IC50 of these DAs, which is correlated to the effective cellular uptake.

Molecular simulation of the shape deformation of a polymersome.

Vesicles composed of diblock copolymers, or polymersomes, have proven to possess numerous applications ranging from drug delivery to catalytically driven nano-motors. The shape of a polymersome can be responsive to external stimuli, such as light or solvent. Molecular dynamics simulations reveal that the shape change upon the contraction of the inner volume of a polymersome vesicle occurs in two separate regimes-a stretching regime and a bending regime.

Interaction of Camptothecin with Model Cellular Membranes.

Accurate and efficient prediction of drug partitioning in model membranes is of significant interest to the pharmaceutical industry. Herein, we utilize advanced sampling methods, specifically, the adaptive biasing force methodology to calculate the potential of mean force for a model hydrophobic anticancer drug, camptothecin (CPT), across three model interfaces. We consider an octanol bilayer, a thick octanol/water interface, and a model 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine (POPC)/water interface.

Rational Coarse-Grained Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

Peptide self-assembly has been used to design an array of nanostructures that possess functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). These DAs have shown to possess an inherently high drug loading with a tunable release mechanism.

Molecular Mechanism for the Role of the H2A and H2B Histone Tails in Nucleosome Repositioning.

The nucleosome core particle (NCP) is the basic packaging unit of DNA. Recently reported structures of the NCP suggest that the histone octamer undergoes conformational changes during the process of DNA translocation around the histone octamer. Herein, we demonstrate with long-time all-atomistic molecular dynamics simulations that the histone tails play a critical role in this nucleosome repositioning.

Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

We report here on long-time all-atomistic molecular dynamics simulations of functional supramolecular nanotubes composed by the self-assembly of peptide-drug amphiphiles (DAs). These DAs have been shown to possess an inherently high drug loading of the hydrophobic anticancer drug camptothecin. We probe the self-assembly mechanism from random with ∼0.

Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers.

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the β subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer.

Glassy worm-like micelles in solvent and shear mediated shape transitions.

The glassiness of polymer melts is generally considered to be suppressed by small dimensions, added solvent, and heat. Here, we suggest that glassiness persists at the nanoscale in worm-like micelles composed of amphiphilic diblock copolymers of poly(ethylene oxide)-polystyrene (PS). The glassiness of these worms is indicated by a lack of fluorescence recovery after photobleaching as well as micron-length rigid segments separated by hinges.

Isomeric control of the mechanical properties of supramolecular filament hydrogels.

Supramolecular filament hydrogels are an emerging class of biomaterials that hold great promise for regenerative medicine, tissue engineering, and drug delivery. However, fine-tuning of their bulk mechanical properties at the molecular level without altering their network structures remains a significant challenge. Here we report an isomeric strategy to construct amphiphilic peptides through the conjugation of isomeric hydrocarbons to influence the local viscoelastic properties of their resulting supramolecular hydrogels.

Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments.

Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J.

Molecular simulations of peptide amphiphiles.

This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles and drug-amphiphiles. The ability to predict the structure and stability of peptide self-assemblies from the molecular level up is vital to the field of nanobiotechnology. Computational methods such as molecular dynamics offer the opportunity to characterize intermolecular forces between peptide-amphiphiles that are critical to the self-assembly process.

Asymmetric breathing motions of nucleosomal DNA and the role of histone tails.

The most important packing unit of DNA in the eukaryotic cell is the nucleosome. It undergoes large-scale structural re-arrangements during different cell cycles. For example, the disassembly of the nucleosome is one of the key steps for DNA replication, whereas reassembly occurs after replication.

- Stacking Mediated Chirality in Functional Supramolecular Filaments.

While a great diversity of peptide-based supra-molecular filaments have been reported, the impact of an auxiliary segment on the chiral assembly of peptides remains poorly understood. Herein we report on the formation of chiral filaments by the self-assembly of a peptide-drug conjugate containing an aromatic drug camptothecin (CPT) in a computational study. We find that the chirality of the filament is mediated by the ‒ stacking between CPTs, not only by the well-expected intermolecular hydrogen bonding between peptide segments.

TCR triggering by pMHC ligands tethered on surfaces via poly(ethylene glycol) depends on polymer length.

Antigen recognition by T cells relies on the interaction between T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) at the interface between the T cell and the antigen presenting cell (APC). The pMHC-TCR interaction is two-dimensional (2D), in that both the ligand and receptor are membrane-anchored and their movement is limited to 2D diffusion. The 2D nature of the interaction is critical for the ability of pMHC ligands to trigger TCR.

Molecular simulation of the concentration-dependent interaction of hydrophobic drugs with model cellular membranes.

We report here the interactions between a hydrophobic drug and a model cellular membrane at the molecular level using all-atom molecular dynamics simulations of paclitaxel, a hydrophobic cancer drug. The calculated free energy of a single drug across the bilayer interface displays a minimum in the outer hydrophobic zone of the membrane. The transfer free energy shows excellent agreement with reported experimental data.

Molecular Simulation of the Transport of Drugs across Model Membranes.

This Perspective describes recent progress in the area of the molecular simulation of the interactions of hydrophobic and hydrophilic solutes with membranes. The ability to predict drug solubility prior to synthesis is an extremely desirable goal for pharmaceutical research. A major advantage of molecular dynamics is the ability to computationally probe both the drug solubility as well as the pathway for the transport of drugs across membranes.

Filomicelles in nanomedicine - from flexible, fragmentable, and ligand-targetable drug carrier designs to combination therapy for brain tumors.

Nanoparticles that are made by self-assembly into non-spherical shapes are promising as drug delivery vehicles. This review focuses on flexible and fragmentable filamentous micelles referred to as filomicelles made of degradable block copolymer amphiphiles. They are inspired by filoviruses and also by tubular proplatelets that break up into smaller platelets in blood flow.

Nanoparticle shape improves delivery: rational coarse grain molecular dynamics (rCG-MD) of taxol in worm-like PEG-PCL micelles.

Nanoparticle shape can improve drug delivery, based in part on recent findings that flexible, worm-like nanocarriers (Worms) increase the amount of drug delivered to tumors and shrink the tumors more effectively than spherical micelles (Spheres). Here, all-atom molecular dynamics (MD) simulations are used to build a rational coarse grain (rCG) model that helps clarify shape-dependent effects in delivery of the widely used anticancer drug Taxol by block copolymer micelles. Potentials for rCG-MD were developed to examine the partitioning of this hydrophobic-aromatic drug into Worms and Spheres that self-assemble in water from poly(ethyleneglycol)-poly(caprolactone) (PEG-PCL), a weakly segregating amphiphile.

Curvature-coupled hydration of Semicrystalline Polymer Amphiphiles yields flexible Worm Micelles but favors rigid Vesicles: polycaprolactone-based block copolymers.

Crystallization processes are in general sensitive to detailed conditions, but our present understanding of underlying mechanisms is insufficient. A crystallizable chain within a diblock copolymer assembly is expected to couple curvature to crystallization and thereby impact rigidity as well as preferred morphology, but the effects on dispersed phases have remained unclear. The hydrophobic polymer polycaprolactone (PCL) is semi-crystalline in bulk (T(m) = 60°C) and is shown here to generate flexible worm micelles or rigid vesicles in water from several dozen polyethyleneoxide-based diblocks (PEO-PCL).