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Molecular recognition binding sites that specifically identify a target molecule are essential for life science research, clinical diagnoses, and therapeutic development. Corona phase molecular recognition is a technique introduced to generate synthetic recognition at the surface of a nanoparticle corona, but it remains an important question whether such entities can achieve the specificity of natural enzymes and receptors. In this work, we generate and screen a library of 24 amphiphilic polymers, preselected for molecular recognition and based on functional monomers including methacrylic acid, acrylic acid, and styrene, iterating upon a poly(methacrylic acid-co-styrene) motif. When complexed to a single-walled carbon nanotube, some of the resulting corona phases demonstrate binding specificity remarkably similar to that of phosphodiesterase type 5 (PDE5), an enzyme that catalyzes the hydrolysis of secondary messenger. The corona phase binds selectively to a PDE5 inhibitor, Vardenafil, as well as its molecular variant, but not to other potential off-target inhibitors. Our work herein examines the specificity and sensitivity of polymer “mutations” to the corona phase, as well as direct competitions with the native binding PDE5. Using structure perturbation, corona surface characterization, and molecular dynamics simulations, we show that the molecular recognition is associated with the unique three-dimensional configuration of the corona phase formed at the nanotube surface. This work conclusively shows that corona phase molecular recognition can mimic key aspects of biological recognition sites and drug targets, opening up possibilities for pharmaceutical and biological applications.

A new type of neutral donor-acceptor [2]-catenane, containing both complementary units in the same ring was synthesized from a dynamic combinatorial library in water. The yield of the water soluble [2]-catenane is enhanced by increasing either building-block concentrations or ionic strength, or by the addition of an electron-rich template. NMR spectroscopy demonstrates that the template is intercalated between the 2 electron-deficient naphthalenediimide units of the catenane.

A thorough, accessible, and general overview of chemosensors Providing a comprehensive overview of chemosensors—organic molecules designed to bind and sense small molecules or metal ions—and their applications, Chemosensors: Principles, Strategies, and Applications is an accessible one-stop resource for analysts, clinicians, and graduate students studying advanced chemistry and chemosensing. Chemosensors function on a molecular level, generating a signal upon binding. The book reviews their synthesis, design, and applications for detecting biological and organic molecules as well as metal ions. The text highlights applications in drug discovery and catalyses that have not been well covered elsewhere. Covering such topics as molecular recognition, detection methods, design strategies, and important biological issues, the book is broken into four sections that examine intermolecular interactions, strategies in sensor design, detection methods, and case studies in metal, saccharide, and amino acid sensing. An indispensable source of information for chemical and biomedical experts using sensors, Chemosensors includes case studies to make the material both accessible and understandable to chemists of all backgrounds.

Potassium channels are among the core functional elements of life because they underpin essential cellular functions including excitability, homeostasis, and secretion. We present here a series of multivalent calix[4]arene ligands that bind to the surface of voltage-dependent potassium channels (Kv1.x) in a reversible manner. Molecular modeling correctly predicts the best candidates with a conical C₄ symmetry for optimal binding, and the effects on channel function are assessed electrophysiologically. Reversible inhibition was observed, without noticeable damage of the oocytes, for tetraacylguanidinium or tetraarginine members of the series with small lower rim O-substituents. Apparent binding constants were in the low micromolar range and had Hill coefficients of 1, consistent with a single site of binding. Suppression of current amplitude was accompanied by a positive shift in the voltage dependence of gating and slowing of both voltage sensor motion and channel opening. These effects are in keeping with expectations for docking in the central pore and interaction with the pore domain \"turret.\"

Plant immune responses often depend on leucine-rich repeat receptors that recognize microbe-associated molecular patterns or pathogen-specific virulence proteins, either directly or indirectly. When the recognition is direct, a molecular arms race takes place where plant receptors continually and rapidly evolve in response to virulence factor evolution. A useful model system to study ligand-receptor coevolution dynamics at the protein level is represented by the interaction between pathogen-derived polygalacturonases (PGs) and plant polygalacturonase-inhibiting proteins (PGIPs). We have applied codon substitution models to PGIP sequences of different eudicotyledonous families to identify putative positively selected sites and then compared these sites with the propensity of protein surface residues to interact with protein partners, based on desolvation energy calculations. The 2 approaches remarkably correlated in pinpointing several residues in the concave face of the leucine-rich repeat domain. These residues were mutated into alanine and their effect on the recognition of several PGs was tested, leading to the identification of unique hotspots for the PGIP-PG interaction. The combined approach used in this work can be of general utility in cases where structural information about a pattern-recognition receptor or resistance-gene product is available.

Computational techniques have been applied in the drug discovery pipeline since the 1980s. Given the low computational resources of the time, the first molecular modeling strategies relied on a rigid view of the ligand-target binding process. During the years, the evolution of hardware technologies has gradually allowed simulating the dynamic nature of the binding event. In this work, we present an overview of the evolution of structure-based drug discovery techniques in the study of ligand-target recognition phenomenon, going from the static molecular docking toward enhanced molecular dynamics strategies.

Cyclic amines can be encapsulated in a water-soluble self-assembled supramolecular host upon protonation. The hydrogen-bonding ability of the cyclic amines, as well as the reduced degrees of rotational freedom, allows for the formation of proton-bound homodimers inside of the assembly that are otherwise not observable in aqueous solution. The generality of homodimer formation was explored with small N-alkyl aziridines, azetidines, pyrrolidines, and piperidines. Proton-bound homodimer formation is observed for N-alkylaziridines (R = methyl, isopropyl, tert-butyl), N-alkylazetidines (R = isopropyl, tert-butyl), and N-methylpyrrolidine. At high concentration, formation of a proton-bound homotrimer is observed in the case of N-methylaziridine. The homodimers stay intact inside the assembly over a large concentration range, thereby suggesting cooperative encapsulation. Both G3(MP2)B3 and G3B3 calculations of the proton-bound homodimers were used to investigate the enthalpy of the hydrogen bond in the proton-bound homodimers and suggest that the enthalpic gain upon formation of the proton-bound homodimers may drive guest encapsulation.

Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein–ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein–ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein–ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or “entropy meter” also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water–protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins.

Microorganisms have evolved to thrive in virtually any terrestrial and marine environment, exposing them to various mechanical cues mainly generated by fluid flow and pressure as well as surface contact. Cellular components enable bacteria to sense and respond to physical cues to optimize their function, ultimately improving bacterial fitness. Owing to newly developed biophysical techniques, we are now starting to appreciate the breadth of bacterial phenotypes influenced by mechanical inputs: adhesion, motility, biofilm formation and pathogenicity. In this Review, we discuss how microbiology and biophysics are converging to advance our understanding of the mechanobiology of microorganisms. We first review the various physical forces that bacteria experience in their natural environments and describe the structures that transmit these forces to a cell. We then discuss how forces can provide feedback to enhance adhesion and motility and how they can be transduced by dedicated cellular machinery to regulate diverse phenotypes. Finally, we provide a perspective on how mechanics influence biofilm spatial organization and homeostasis.Microbiology and biophysics are converging to advance our understanding of the mechanobiology of microorganisms. In this Review, Dufrêne and Persat discuss the physical forces that bacteria experience in their natural environments and the structures that transmit these forces to a cell. Furthermore, they explore bacterial phenotypes influenced by mechanical inputs, including adhesion, motility and biofilm formation.

The recently emerged coronavirus designated as SARS-CoV-2 (also known as 2019 novel coronavirus (2019-nCoV) or Wuhan coronavirus) is a causative agent of coronavirus disease 2019 (COVID-19), which is rapidly spreading throughout the world now. More than 1.21 million cases of SARS-CoV-2 infection and more than 67,000 COVID-19-associated mortalities have been reported worldwide till the writing of this article, and these numbers are increasing every passing hour. The World Health Organization (WHO) has declared the SARS-CoV-2 spread as a global public health emergency and admitted COVID-19 as a pandemic now. Multiple sequence alignment data correlated with the already published reports on SARS-CoV-2 evolution indicated that this virus is closely related to the bat severe acute respiratory syndrome-like coronavirus (bat SARS-like CoV) and the well-studied human SARS coronavirus (SARS-CoV). The disordered regions in viral proteins are associated with the viral infectivity and pathogenicity. Therefore, in this study, we have exploited a set of complementary computational approaches to examine the dark proteomes of SARS-CoV-2, bat SARS-like, and human SARS CoVs by analysing the prevalence of intrinsic disorder in their proteins. According to our findings, SARS-CoV-2 proteome contains very significant levels of structural order. In fact, except for nucleocapsid, Nsp8, and ORF6, the vast majority of SARS-CoV-2 proteins are mostly ordered proteins containing less intrinsically disordered protein regions (IDPRs). However, IDPRs found in SARS-CoV-2 proteins are functionally important. For example, cleavage sites in its replicase 1ab polyprotein are found to be highly disordered, and almost all SARS-CoV-2 proteins contains molecular recognition features (MoRFs), which are intrinsic disorder-based protein–protein interaction sites that are commonly utilized by proteins for interaction with specific partners. The results of our extensive investigation of the dark side of SARS-CoV-2 proteome will have important implications in understanding the structural and non-structural biology of SARS or SARS-like coronaviruses.