Inspection on the Mechanism of SARS-CoV-2 Inhibition by Penciclovir: A Molecular Dynamic Study.

In recent years, humanity has had to face a critical pandemic due to SARS-CoV-2. In the rapid search for effective drugs against this RNA-positive virus, the repurposing of already existing nucleotide/nucleoside analogs able to stop RNA replication by inhibiting the RNA-dependent RNA polymerase enzyme has been evaluated. In this process, a valid contribution has been the use of in silico experiments, which allow for a rapid evaluation of the possible effectiveness of the proposed drugs. Here we propose a molecular dynamic study to provide insight into the inhibition mechanism of Penciclovir, a nucleotide analog on the RNA-dependent RNA polymerase enzyme. Besides the presented results, in this article, for the first time, molecular dynamic simulations have been performed considering not only the RNA-dependent RNA polymerase protein, but also its cofactors (fundamental for RNA replication) and double-strand RNA.

Protection against proteolysis of a targeting peptide on gold nanostructures.

Cell targeting has been considered an important strategy in diagnostic and therapeutic applications. Among different targeting units, peptides have emerged for their ability to bind to many different cellular targets, their scarce immunogenicity and the possibility of introducing multiple copies on nanosystems, providing high avidity for the target. However, their sensitivity to proteases strongly limits their applications in vivo. Here, we show that when presented on the surface of nanostructures, peptide stability to proteolysis is strongly improved without reducing the targeting activity. We prepared plasmonic nanostructures functionalized with a dodecapeptide (GE11) which targets EGFR, a protein overexpressed on different types of tumors. Two types of nanosystems were prepared in which the targeting unit was either directly linked to gold nanoparticles or through a PEG chain, resulting in a different peptide density on the surface of nanostructures. The peptide was rapidly degraded in 20% human serum or in the presence of isolated serine proteases, whereas no significant proteolytic fragments were detected during incubation of the nanosystems and after 24 h digestion, the nanostructures maintained their targeting activity and selectivity on colon cancer cells. Molecular dynamic calculations of the interaction of the nanostructure with chymotrypsin suggest that the formation of the enzyme-peptide complex, the first step in the mechanism of peptide hydrolysis, is highly unlikely because of the constraint imposed by the link of the peptide to the nanoparticle. These results support the utilization of peptides as active targeting units in nanomedicine.

From nanoaggregates to mesoscale ribbons: the multistep self-organization of amphiphilic peptides.

This paper reports atomic force microscopy results and molecular dynamics simulations of the striking differences of long-term self-organization structures of negatively charged (AcA4)2KD (double tail) and AcA4D (single tail) peptides, respectively, forming micrometer-long, linearly ordered ribbon-like structures and nanometer-sized, unstructured, round-shaped aggregates. The subsequent formation steps of the long-range nanoribbons, experimentally observed only for the "double tail" (AcA4)2KD peptide, are analyzed in detail, showing that the initial "primary" unstructured round-shaped aggregates progressively evolve into longer nanofilaments and into micrometer-long, network-forming nanoribbon moieties. In particular, the long-range self-organization of the "double tail" peptides appears to be closely related to electrostatically driven diffusional motions of the primary aggregates and nanofilaments. The diffusional freedom degrees are prompted by the formation of a dynamic ternary air/liquid/substrate interface, due to the water evaporation process from the ultrathin films of the peptide solution cast onto a solid mica substrate. Overall, the initial aggregation of unstructured round-shaped moieties, for both the peptides, can be seen as an entropy-driven process, involving the intra- and intermolecular interactions of hydrophobic parts of the peptides, while the further formation of long nanoribbons, only for "double tail" peptides, can be viewed in terms of an enthalpy-driven process, mainly due to the predominant electrostatic interactions between the charged heads of the interacting peptides. The role of the solid-liquid interface, as the locus of the enthalpy-driven linear organization, is also highlighted.

Coarse-Grained Simulation of the Adsorption of Water on Au(111) Surfaces Using a Modified Stillinger-Weber Potential.

For reproducing the behavior of water molecules adsorbed on gold surfaces in terms of density of both bulk and interfacial water and in terms of structuring of water on top of gold atoms, the implementation of a multibody potential is necessary, thus the Stillinger-Weber potential was tested. The goal is using a single nonbonded potential for coarse-grained models, without the usage of explicit charges. In order to modify the angular part of the Stillinger-Weber potential from a single cosine to a piecewise function accounting for multiple equilibrium angles, employed for Au-Au-Au and Au-Au-water triplets, it is necessary to create a version of the simulation package LAMMPS that supports the assignment of multiple favored angles. This novel approach is able to reproduce the data obtained using quantum mechanical calculations and density profiles of both bulk and adsorbed water molecules obtained using classical polarizable force fields.

Understanding the good and poor cell targeting activity of gold nanostructures functionalized with molecular units for the epidermal growth factor receptor.

Nanostructures can strongly interact with cells or other biological structures; furthermore when they are functionalized with targeting units, they are of great interest for a variety of applications in the biotechnology field like those for efficient imaging, diagnosis and therapy and in particular for cancer theranostics. Obtaining targeting with good specificity and sensitivity is a key necessity, which, however, is affected by the complexity of the interactions between the nanostructures and the biological components. In this work we report the study of specificity and sensitivity of gold nanoparticles functionalized with the peptide GE11 for the targeting of the epidermal growth factor receptor, expressed on many cells and, in particular, on many types of cancer cells. We show how a combination of spectroscopic measurements and molecular dynamics simulations allows the comprehension of the targeting activity of peptides linked to the surface of gold nanostructures and how the targeting is tuned by the presence of polyethylene glycol chains.