Structure and dynamics of the interaction of Delta and Omicron BA.1 SARS-CoV-2 variants with REGN10987 Fab reveal mechanism of antibody action.

Study of mechanisms by which antibodies recognize different viral strains is necessary for the development of new drugs and vaccines to treat COVID-19 and other infections. Here, we report 2.5 Å cryo-EM structure of the SARS-CoV-2 Delta trimeric S-protein in complex with Fab of the recombinant analog of REGN10987 neutralizing antibody.

Membrane-mediated interaction of non-conventional snake three-finger toxins with nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptor of α7 type (α7-nAChR) presented in the nervous and immune systems and epithelium is a promising therapeutic target for cognitive disfunctions and cancer treatment. Weak toxin from Naja kaouthia venom (WTX) is a non-conventional three-finger neurotoxin, targeting α7-nAChR with weak affinity. There are no data on interaction mode of non-conventional neurotoxins with nAChRs.

A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain.

Understanding fusion mechanisms employed by SARS-CoV-2 spike protein entails realistic transmembrane domain (TMD) models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD only based on its primary structure. We performed amino acid sequence pattern matching and compared the molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and selected an appropriate template for homology modeling.

Structure-based rational design of an enhanced fluorogen-activating protein for fluorogens based on GFP chromophore.

"Fluorescence-Activating and absorption-Shifting Tag" (FAST) is a well-studied fluorogen-activating protein with high brightness and low size, able to activate a wide range of fluorogens. This makes FAST a promising target for both protein and fluorogen optimization. Here, we describe the structure-based rational design of the enhanced FAST mutants, optimized for the N871b fluorogen.

Characterization of the Corynebacterium glutamicum dehydroshikimate dehydratase QsuB and its potential for microbial production of protocatechuic acid.

The dehydroshikimate dehydratase (DSD) from Corynebacterium glutamicum encoded by the qsuB gene is related to the previously described QuiC1 protein (39.9% identity) from Pseudomonas putida. Both QuiC1 and QsuB are two-domain bacterial DSDs.

Environmental and dynamic effects explain how nisin captures membrane-bound lipid II.

Antibiotics (AB) resistance is a major threat to global health, thus the development of novel AB classes is urgently needed. Lantibiotics (i.e.

Specific refolding pathway of viscumin A chain in membrane-like medium reveals a possible mechanism of toxin entry into cell.

How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simulations have been used to explore large-scale conformational changes of the globular viscumin A chain in a complex environment - comprising urea and chloroform/methanol (CHCl/MeOH) mixture. Being well-packed in aqueous solution, viscumin A undergoes global structural rearrangements in both organic media.

Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains.

Heat-activated transient receptor potential channel TRPV1 is one of the most studied eukaryotic proteins involved in temperature sensation. Upon heating, it exhibits rapid reversible pore gating, which depolarizes neurons and generates action potentials. Underlying molecular details of such effects in the pore region of TRPV1 is of a crucial importance to control temperature responses of the organism.

PREDDIMER: a web server for prediction of transmembrane helical dimers.

Summary: Here we present PREDDIMER, a web tool for prediction of dimer structure of transmembrane (TM) helices. PREDDIMER allows (i) reconstruction of a number of dimer structures for given sequence(s) of TM protein fragments, (ii) ranking and filtering of predicted structures according to respective values of a scoring function, (iii) visualization of predicted 3D dimer structures and (iv) visualization of surface hydrophobicity of TM helices and their contacting (interface) regions represented as 2D maps.

Results: We implemented online the original PREDDIMER algorithm and benchmarked the server on 11 TM sequences, whose 3D dimer conformations were obtained previously by nuclear magnetic resonance spectroscopy.

Lipid-II forms potential "landing terrain" for lantibiotics in simulated bacterial membrane.

Bacterial cell wall is targeted by many antibiotics. Among them are lantibiotics, which realize their function via interaction with plasma membrane lipid-II molecule - a chemically conserved part of the cell wall synthesis pathway. To investigate structural and dynamic properties of this molecule, we have performed a series of nearly microsecond-long molecular dynamics simulations of lipid-II and some of its analogs in zwitterionic single component and charged mixed simulated phospholipid bilayers (the reference and the mimic of the bacterial plasma membrane, respectively).

Dynamic clustering of lipids in hydrated two-component membranes: results of computer modeling and putative biological impact.

Delineation and analysis of lateral clustering of lipids in model bilayers is an important step toward understanding of the physical processes underlying formation of lipid domains and rafts in cell membranes. Computer modeling methods represent a powerful tool to address the problem since they can detect clusters of only few lipid molecules - this issue still resists easy characterization with modern experimental techniques. In this work, we propose a computational method to detect and analyze parts of membrane with different packing densities and hydrogen bonding patterns.

PLATINUM: a web tool for analysis of hydrophobic/hydrophilic organization of biomolecular complexes.

Unlabelled: The PLATINUM (Protein-Ligand ATtractions Investigation NUMerically) web service is designed for analysis and visualization of hydrophobic/hydrophilic properties of biomolecules supplied as 3D-structures. Furthermore, PLATINUM provides a number of tools for quantitative characterization of the hydrophobic/hydrophilic match in biomolecular complexes e.g.

The membrane-proximal fusion domain of HIV-1 GP41 reveals sequence-specific and fine-tuning mechanism of membrane binding.

The membrane interface-partitioning region preceding the transmembrane anchor of the human immunodeficiency virus type 1 (HIV-1) gp41 envelope protein is one of the sites responsible for virus binding to its host cell membrane and subsequent fusion events. Here, we used molecular modeling techniques to assess membrane interactions, structure, and hydrophobic properties of the fusion-active peptide representing this region, several of its homologs from different HIV-1 strains, as well as a peptide - defective gp41 phenotype - unable to mediate cell-cell fusion and virus entry. It is shown that the wild-type peptides bind to the water-membrane interface in alpha-helical conformation, while the mutant adopts partly destabilized helix-break-helix structure on the membrane surface.

Specificity of helix packing in transmembrane dimer of the cell death factor BNIP3: a molecular modeling study.

BNIP3 is a mitochondrial 19-kDa proapoptotic protein, a member of the Bcl-2 family. It has a single COOH-terminal transmembrane (TM) alpha-helical domain, which is required for membrane targeting, proapoptotic activity, hetero- and homo-dimerization in membrane. The role and the molecular details of association of TM helices of BNIP3 are yet to be established.

Method to assess packing quality of transmembrane alpha-helices in proteins. 2. Validation by "correct vs misleading" test.

We describe a set of tests designed to check the ability of the new "membrane score" method (see the first paper of this series) to assess the packing quality of transmembrane (TM) alpha-helical domains in proteins. The following issues were addressed: (1) Whether there is a relation between the score (S(mem)) of a model and its closeness to the "nativelike" conformation? (2) Is it possible to recognize a correct model among misfolded and erroneous ones? (3) To what extent the score of a homology-built model is sensitive to errors in sequence alignment? To answer the first question, two test cases were considered: (i) Several models of bovine aquaporin-1 (target protein) were built on the structural templates provided by its homologs with known X-ray structure. (ii) Side chains in the spatial models of visual rhodopsin and cytochrome c oxidase were rebuilt based on the backbone scaffolds taken from their crystal structures, and the resulting models were iteratively fitted into the full-atom X-ray conformations.

Method to assess packing quality of transmembrane alpha-helices in proteins. 1. Parametrization using structural data.

Integral membrane proteins (MPs) are pharmaceutical targets of exceptional importance. Modern methods of three-dimensional protein structure determination often fail to supply the fast growing field of structure-based drug design with the requested MPs' structures. That is why computational modeling techniques gain a special importance for these objects.

Role of lipid charge in organization of water/lipid bilayer interface: insights via computer simulations.

Anionic unsaturated lipid bilayers represent suitable model systems that mimic real cell membranes: they are fluid and possess a negative surface charge. Understanding of detailed molecular organization of water-lipid interfaces in such systems may provide an important insight into the mechanisms of proteins' binding to membranes. Molecular dynamics (MD) of full-atom hydrated lipid bilayers is one of the most powerful tools to address this problem in silico.

Association of transmembrane helices: what determines assembling of a dimer?

Self-association of two hydrophobic alpha-helices is studied via unrestrained Monte Carlo (MC) simulations in a hydrophobic slab described by an effective potential. The system under study represents two transmembrane (TM) segments of human glycophorin A (GpA), which form homo-dimers in membranes. The influence of TM electrostatic potential, thickness and hydrophobicity degree of lipid bilayer is investigated.

Helix Interactions in Membranes: Lessons from Unrestrained Monte Carlo Simulations.

We describe one of the first attempts at unrestrained modeling of self-association of α-helices in implicit heterogeneous membrane-mimic media. The computational approach is based on the Monte Carlo conformational search for peptides in dihedral angles space. The membrane is approximated by an effective potential.

Peptides and proteins in membranes: what can we learn via computer simulations?

Membrane and membrane-active peptides and proteins play a crucial role in numerous cell processes, such as signaling, ion conductance, fusion, and others. Many of them act as highly specific and efficient drugs or drug targets, and, therefore, attract growing interest of medicinal chemists. Because of experimental difficulties with characterization of their spatial structure and mode of membrane binding, essential attention is given now to molecular modeling techniques.

The New York State Health Care Proxy Law and the issue of artificial hydration and nutrition.

The New York State Health Care Proxy (HCP) Law allows a surrogate to make medical decisions for an individual when he or she loses the capacity to make them. In the area of artificial hydration and nutrition, however, this law dictates that if the agent is not aware of the patient's wishes regarding hydration and nutrition, the agent cannot decide about this treatment.

Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations.

WNDP (Wilson's disease protein) is a copper-transporting ATPase that plays an essential role in human physiology. Mutations in WNDP result in copper accumulation in tissues and cause a severe hepato-neurological disorder known as Wilson's disease. Several mutations were surmised to affect the nucleotide binding and hydrolysis by WNDP; however, how the nucleotides bind to normal and mutated WNDP remains unknown.

Monte Carlo simulations of voltage-driven translocation of a signal sequence.

Transmembrane potentials play important but poorly understood roles in many biological processes, including signal sequence-mediated protein translocation across bacterial membranes. In this study we applied Monte Carlo techniques to simulate the way the potential acts on a signal sequence. The simulations demonstrate that in the absence of a potential the signal sequence prefers insertion in both helical hairpin and transmembrane alpha-helical conformations.

Interaction of cardiotoxins with membranes: a molecular modeling study.

Incorporation of beta-sheet proteins into membrane is studied theoretically for the first time, and the results are validated by the direct experimental data. Using Monte Carlo simulations with implicit membrane, we explore spatial structure, energetics, polarity, and mode of insertion of two cardiotoxins with different membrane-destabilizing activity. Both proteins, classified as P- and S-type cardiotoxins, are found to retain the overall "three-finger" fold interacting with membrane core and lipid/water interface by the tips of the "fingers" (loops).

[Modeling of peptides and proteins in a membrane environment.II. Structural and energetic aspects of Glycophorin A in a lipid bilayer].

The conformational space of a hydrophobic peptide fragment of glycophorin A in a lipid membrane was studied with the Monte Carlo method using the solvation model described in the first communication of this series. The simulation was performed for various starting orientations of the peptide relative to the membrane bilayer: outside, inside, partially immersed, and transbilayer. We showed that the membrane substantially stabilizes the alpha-helical conformation of the central hydrophobic part of the glycophorin A molecule, which for the most part is immersed in the apolar core of the bilayer.