Entropic repulsion of cholesterol-containing layers counteracts bioadhesion.

Control of adhesion is a striking feature of living matter that is of particular interest regarding technological translation1-3. We discovered that entropic repulsion caused by interfacial orientational fluctuations of cholesterol layers restricts protein adsorption and bacterial adhesion. Moreover, we found that intrinsically adhesive wax ester layers become similarly antibioadhesive when containing small quantities (under 10 wt%) of cholesterol. Wetting, adsorption and adhesion experiments, as well as atomistic simulations, showed that repulsive characteristics depend on the specific molecular structure of cholesterol that encodes a finely balanced fluctuating reorientation at the interface of unconstrained supramolecular assemblies: layers of cholesterol analogues differing only in minute molecular variations showed markedly different interfacial mobility and no antiadhesive effects. Also, orientationally fixed cholesterol layers did not resist bioadhesion. Our insights provide a conceptually new physicochemical perspective on biointerfaces and may guide future material design in regulation of adhesion.

Transferability of different classical force fields for right and left handed α-helices constructed from enantiomeric amino acids.

Amino acids can form d and l enantiomers, of which the l enantiomer is abundant in nature. The naturally occurring l enantiomer has a greater preference for a right handed helical conformation, and the d enantiomer for a left handed helical conformation. The other conformations, that is, left handed helical conformations of the l enantiomers and right handed helical conformations of the d enantiomers, are not common. The energetic differences between left and right handed alpha helical peptide chains constructed from enantiomeric amino acids are investigated using quantum chemical calculations (using the M06/6-311g(d,p) level of theory). Further, the performances of commonly used biomolecular force fields (OPLS/AA, CHARMM27/CMAP and AMBER) to represent the different helical conformations (left and right handed) constructed from enantiomeric (D and L) amino acids are evaluated. 5- and 10-mer chains from d and l enantiomers of alanine, leucine, lysine, and glutamic acid, in right and left handed helical conformations, are considered in the study. Thus, in total, 32 α-helical polypeptides (4 amino acids × 4 conformations of 5-mer and 10-mer) are studied. Conclusions, with regards to the performance of the force fields, are derived keeping the quantum optimized geometry as the benchmark, and on the basis of phi and psi angle calculations, hydrogen bond analysis, and different long range helical order parameters.

Vesicle structures from bolaamphiphilic biosurfactants: experimental and molecular dynamics simulation studies on the effect of unsaturation on sophorolipid self-assemblies.

The formation of giant-vesicle-like structures by self-assembling linolenic acid sophorolipid (LNSL) molecules is revealed. Sophorolipids belong to the class of bolaamphiphilic glycolipid biosurfactants. Interestingly, the number of double bonds present in the hydrophobic core of sophorolipids is seen to have a great influence on the type of self-assembled structures formed. Dye encapsulation results establish the presence of an aqueous compartment inside the LNSL vesicles. Molecular dynamics simulation (MD) studies suggest the existence of two possible conformations of LNSLs inside the self-assembled structures and that LNSL molecules arrange in layered structures.

Model atomistic protrusions favouring the ordering and retention of water.

The ordering of water molecules near model linear atomistic protrusions is studied using classical molecular dynamics simulations. The protrusions are made up of Lennard-Jones particles of hydrophobic and hydrophilic blocks. Simulations are performed at a range of temperatures and pressures, keeping the position of the protrusions fixed. At different temperatures and pressures, the ordering and residence time of water molecules is enhanced on the surface of the hydrophilic block. Detailed analysis of the systems shows that the surface region is potentially the most energetically favorable for water molecules, which is consistent with the tetrahedral ordering of water molecules. A competition between energetics and structuring is observed from residence time calculations.

Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy.

A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer.

Propensity of Self-Assembled Leucine-Lysine Diblock Copolymeric α-Helical Peptides To Remain in Parallel and Antiparallel Alignments in Water.

Molecular dynamics simulation study of α-helical diblock copolypeptides preassembled in parallel and antiparallel alignments in water are presented. The assembled peptide lamellar structures were not disrupted even after performing three-step simulation protocols. Primarily hydrogen bonds between peptide are responsible for the stability. The analysis of the trajectory also suggests that water plays a significant role in favoring self-assembly. We have detected continuous hydrogen bonded network structure, which is further responsible for the stability of the lamellar structures. We have performed a detailed analysis of the hydrogen bonded network structure and its length. Further, free energy calculations revealed that the degree of stability for both lamellae are similar. The present study provides structural insight into the stability of self-assembled structures of block copolypeptides.

Distinctions in early stage unwinding mechanisms of zwitterionic, capped, and neutral forms of different α-helical homopolymeric peptides.

Molecular dynamics simulations of α-helical polyalanine, polyleucine, polylysine, and poly(glutamic acid) with different forms of terminal groups in water at 300 K showed sharp distinctions in their unwinding mechanisms. Zwitterionic, capped, and neutral forms of polyalanine, polyleucine, and polylysine have been explored to elucidate their unwinding mechanism at very early stage, e.g., initial time window. Role of water in the unwinding mechanisms of the various helices has been envisaged. Also, it is evident from our calculations that the short- and long-range nonbonded interactions among the side chains is an important factor determining the unwinding mechanisms of the various homopolymeric α-helices. These findings can be helpful in constructing predictive models for understanding of the unwinding of α-helical proteins and peptides.

Molecular dynamics simulation of phosphoric acid doped monomer of polybenzimidazole: a potential component polymer electrolyte membrane of fuel cell.

Phosphoric acid doped polybenzimidazole is promising electrolyte membranes for high temperature (100 °C and above) fuel cells. Proton conduction is governed by the amount of phosphoric acid content in the polymer membrane. In this present work, we perform molecular dynamics simulations on phosphoric acid doped 2-phenyl-1H,1'H-5,5'-bibenzo[d]imidazole (monomer unit of polybenzimidazole) to characterize the structural and dynamical properties at varying phosphoric acid content and temperature. From the structural analysis, we have predicted the arrangement of the phosphoric acids, formation of H-bonds in the system, and the contribution of different atoms toward H-bonding. We have also examined the stacking of 2-phenyl-1H,1'H-5,5'-bibenzo[d]imidazole molecules and how their arrangement changes with the increasing amount of PA in the system with the help of cluster analysis. From the molecular dynamics simulation conducted at different temperatures and phosphoric acid doping level, we have predicted the diffusion of phosphoric acid and monomer. As a dynamic quantity, we have also calculated ring flipping of the imidazole ring of the monomer.

Headgroup mediated water insertion into the DPPC bilayer: a molecular dynamics study.

Molecular dynamics simulation was performed on the 1,2-dipalmitoyl-sn-phosphocholine (DPPC) bilayer-water system using the GROMOS96 53a6 united atom force field. The transferability of force field was tested by reproducing the area per lipid within 3% accuracy from the experimental value. The simulation shows that water can penetrate much deeper inside the bilayer almost up to the starting point of the aliphatic chain. There is significant evidence from experiments that water goes deep in the DPPC bilayer, but it has not been reported from theoretical work. The mechanism of insertion of water deep inside the lipid bilayer is still not clear. In this report, for the first time, the mechanism of water insertion deep into the bilayer has been proposed. Water transport occurs by the headgroup and its first solvation shell. The trimethyl ammonium (NMe(3)) group (headgroup of DPPC) has two stable conformations at the bilayer-water interface, one outside the bilayer and another inside it. The NMe(3) group has a large clustering of water around it and takes the water molecules inside the bilayer with it during its entry into the bilayer. The water molecules penetrate into the bilayer with the help of the NMe(3) group present at the headgroup of DPPC and eventually form hydrogen bonds with carbonyl oxygen present deep inside the bilayer. Structural characteristics at the bilayer-water interface region are also reported.