Colabind: A Cloud-Based Approach for Prediction of Binding Sites Using Coarse-Grained Simulations with Molecular Probes.

Binding site prediction is a crucial step in understanding protein-ligand and protein-protein interactions (PPIs) with broad implications in drug discovery and bioinformatics. This study introduces Colabind, a robust, versatile, and user-friendly cloud-based approach that employs coarse-grained molecular dynamics simulations in the presence of molecular probes, mimicking fragments of drug-like compounds. Our method has demonstrated high effectiveness when validated across a diverse range of biological targets spanning various protein classes, successfully identifying orthosteric binding sites, as well as known druggable allosteric or PPI sites, in both experimentally determined and AI-predicted protein structures, consistently placing them among the top-ranked sites.

Nearly complete structure of bacteriophage DT57C reveals architecture of head-to-tail interface and lateral tail fibers.

The T5 family of viruses are tailed bacteriophages characterized by a long non-contractile tail. The bacteriophage DT57C is closely related to the paradigmal T5 phage, though it recognizes a different receptor (BtuB) and features highly divergent lateral tail fibers (LTF). Considerable portions of T5-like phages remain structurally uncharacterized.

Computational Analysis of Mutations in the Receptor-Binding Domain of SARS-CoV-2 Spike and Their Effects on Antibody Binding.

Currently, SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) is responsible for one of the most deleterious pandemics of our time. The interaction between the ACE2 receptors at the surface of human cells and the viral Spike (S) protein triggers the infection, making the receptor-binding domain (RBD) of the SARS-CoV-2 S-protein a focal target for the neutralizing antibodies (Abs). Despite the recent progress in the development and deployment of vaccines, the emergence of novel variants of SARS-CoV-2 insensitive to Abs produced in response to the vaccine administration and/or monoclonal ones represent a potential danger.

Mechanisms of Formation, Structure, and Dynamics of Lipoprotein Discs Stabilized by Amphiphilic Copolymers: A Comprehensive Review.

Amphiphilic copolymers consisting of alternating hydrophilic and hydrophobic units account for a major recent methodical breakthrough in the investigations of membrane proteins. Styrene-maleic acid (SMA), diisobutylene-maleic acid (DIBMA), and related copolymers have been shown to extract membrane proteins directly from lipid membranes without the need for classical detergents. Within the particular experimental setup, they form disc-shaped nanoparticles with a narrow size distribution, which serve as a suitable platform for diverse kinds of spectroscopy and other biophysical techniques that require relatively small, homogeneous, water-soluble particles of separate membrane proteins in their native lipid environment.

Ambiguities in and completeness of SAS data analysis of membrane proteins: the case of the sensory rhodopsin II-transducer complex.

Membrane proteins (MPs) play vital roles in the function of cells and are also major drug targets. Structural information on proteins is vital for understanding their mechanism of function and is critical for the development of drugs. However, obtaining high-resolution structures of membrane proteins, in particular, under native conditions is still a great challenge.

Synergistic Effect of Chemical Penetration Enhancers on Lidocaine Permeability Revealed by Coarse-Grained Molecular Dynamics Simulations.

The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs-linoleic acid (LA) and ethanol-through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid.

Molecular model of a sensor of two-component signaling system.

Two-component systems (TCS) are widespread signaling systems present in all domains of life. TCS typically consist of a signal receptor/transducer and a response regulator. The receptors (histidine kinases, chemoreceptors and photoreceptors) are often embedded in the membrane and have a similar modular structure.

CPE-DB: An Open Database of Chemical Penetration Enhancers.

The cutaneous delivery route currently accounts for almost 10% of all administered drugs and it is becoming more common. Chemical penetration enhancers (CPEs) increase the transport of drugs across skin layers by different mechanisms that depend on the chemical nature of the penetration enhancers. In our work, we created a chemical penetration enhancer database (CPE-DB) that is, to the best of our knowledge, the first CPE database.

Using a viral 2A peptide-based strategy to reconstruct the bovine P450scc steroidogenic system in S. cerevisiae: Bovine P450scc system expression using 2A peptides.

Cytochrome P450scc system performs the first rate-limiting stage of steroidogenesis in mammals. The bovine P450scc system was reconstructed in Saccharomyces cerevisiae, using a foot-and-mouth disease virus 2A peptide (F2A)-based construct, to co-express cytochrome P450scc, adrenodoxin (Adx), and adrenodoxin reductase (AdR). During the translation of the self-processing fusion protein P450scc-F2A-Adx-F2A-AdR, the first and the second linkers are cleaved with different efficiencies (96 % and 11 %, respectively), resulting in the unbalanced expression of individual proteins.

Radioprotectors.org: an open database of known and predicted radioprotectors.

The search for radioprotectors is an ambitious goal with many practical applications. Particularly, the improvement of human radioresistance for space is an important task, which comes into view with the recent successes in the space industry. Currently, all radioprotective drugs can be divided into two large groups differing in their effectiveness depending on the type of exposure.

Lipid dynamics in nanoparticles formed by maleic acid-containing copolymers: EPR spectroscopy and molecular dynamics simulations.

Amphiphilic maleic acid-containing copolymers account for a recent methodical breakthrough in the study of membrane proteins. Their application enables a detergent-free extraction of membrane proteins from lipid bilayers, yielding stable water-soluble, discoidal lipid bilayer particles with incorporated proteins, which are wrapped with copolymers. Although many studies confirm the potential of this approach for membrane protein research, the interactions between the maleic acid-containing copolymers and extracted lipids, as well as possible effects of the copolymers on lipid-embedded proteins deserve further scrutinization.

Mechanical properties of tubulin intra- and inter-dimer interfaces and their implications for microtubule dynamic instability.

Thirteen tubulin protofilaments, made of αβ-tubulin heterodimers, interact laterally to produce cytoskeletal microtubules. Microtubules exhibit the striking property of dynamic instability, manifested in their intermittent growth and shrinkage at both ends. This behavior is key to many cellular processes, such as cell division, migration, maintenance of cell shape, etc.

Replicative and radiation-induced aging: a comparison of gene expression profiles.

All living organisms are subject to the aging process and experience the effect of ionizing radiation throughout their life. There have been a number of studies that linked ionizing radiation process to accelerated aging, but comprehensive signalome analysis of both processes was rarely conducted. Here we present a comparative signaling pathway based analysis of the transcriptomes of fibroblasts irradiated with different doses of ionizing radiation, replicatively aged fibroblasts and fibroblasts collected from young, middle age and old patients.

Styrene/Maleic Acid Copolymers Form SMALPs by Pulling Lipid Patches out of the Lipid Bilayer.

Amphiphilic copolymers composed of styrene and maleic acid (SMA) monomers caused a major methodical breakthrough in the study of membrane proteins. They were found to directly release phospholipids and membrane proteins both from artificial and natural lipid bilayers, yielding stable water-soluble discoidal SMA/lipid particles (SMALPs) of uniform size. Although many empirical studies indicate the great potency of SMALPs for membrane protein research, the mechanisms of their formation remain obscure.

Molecular Mechanism of Uptake of Cationic Photoantimicrobial Phthalocyanine across Bacterial Membranes Revealed by Molecular Dynamics Simulations.

Phthalocyanines are aromatic macrocyclic compounds, which are structurally related to porphyrins. In clinical practice, phthalocyanines are used in fluorescence imaging and photodynamic therapy of cancer and noncancer lesions. Certain forms of the substituted polycationic metallophthalocyanines have been previously shown to be active in photodynamic inactivation of both Gram-negative and Gram-positive bacteria; one of them is zinc octakis(cholinyl)phthalocyanine (ZnPcChol).

Signaling and Adaptation Modulate the Dynamics of the Photosensoric Complex of Natronomonas pharaonis.

Motile bacteria and archaea respond to chemical and physical stimuli seeking optimal conditions for survival. To this end transmembrane chemo- and photoreceptors organized in large arrays initiate signaling cascades and ultimately regulate the rotation of flagellar motors. To unravel the molecular mechanism of signaling in an archaeal phototaxis complex we performed coarse-grained molecular dynamics simulations of a trimer of receptor/transducer dimers, namely NpSRII/NpHtrII from Natronomonas pharaonis.

Comparative computational study of interaction of C60-fullerene and tris-malonyl-C60-fullerene isomers with lipid bilayer: relation to their antioxidant effect.

Oxidative stress induced by excessive production of reactive oxygen species (ROS) has been implicated in the etiology of many human diseases. It has been reported that fullerenes and some of their derivatives-carboxyfullerenes-exhibits a strong free radical scavenging capacity. The permeation of C60-fullerene and its amphiphilic derivatives-C3-tris-malonic-C60-fullerene (C3) and D3-tris-malonyl-C60-fullerene (D3)-through a lipid bilayer mimicking the eukaryotic cell membrane was studied using molecular dynamics (MD) simulations.