Chirality transmission in macromolecular domains

Chiral communications exist in secondary structures of foldamers and copolymers via a network of noncovalent interactions within effective intermolecular force (IMF) range. It is not known whether long-range chiral communication exists between macromolecular tertiary structures such as peptide coiled-coils beyond the IMF distance. Harnessing the high sensitivity of single-molecule force spectroscopy, we investigate the chiral interaction between covalently linked DNA duplexes and peptide coiled-coils by evaluating the binding of a diastereomeric pair of three DNA-peptide conjugates. We find that right-handed DNA triple helices well accommodate peptide triple coiled-coils of the same handedness, but not with the left-handed coiled-coil stereoisomers. This chiral communication is effective in a range (<4.5 nm) far beyond canonical IMF distance. Small-angle X-ray scattering and molecular dynamics simulation indicate that the interdomain linkers are tightly packed via hydrophobic interactions, which likely sustains the chirality transmission between DNA and peptide domains. Our findings establish that long-range chiral transmission occurs in tertiary macromolecular domains, explaining the presence of homochiral pairing of superhelices in proteins.

Recent Developments of Coumarin-based Hybrids in Drug Discovery

Coumarin scaffold is a highly significant O-heterocycle, namely benzopyran-2-ones, form an elite class of naturally occurring compounds that possess promising therapeutic perspectives. Based on its broad spectrum of biological activities, the privileged coumarin scaffold is applied to medicinal and pharmacological treatments by several rational design strategies and approaches. Structure-activity relationships of the coumarin-based hybrids with various bioactivity fragments revealed significant information toward the further development of highly potent and selective disorder therapeutic agents. The molecular docking studies between coumarins and critical therapeutic enzymes demonstrated mode of action by forming noncovalent interactions with more than one receptor, further rationally confirm information about structure-activity relationships. This review summarizes recent developments relating to coumarin-based hybrids with other pharmacophores aiming to numerous feasible therapeutic enzymatic targets to combat various therapeutic fields, including anticancer, antimicrobic, anti-Alzheimer, anti-inflammatory activities.

Towards a Density-Based Description of Chemical Bonds and Noncovalent Interactions with Pauli Energy

Chemical bonds and noncovalent interactions are extraordinarily important concepts in chemistry and beyond. Using density-based quantities to describe them has a long history in the literature, yet none can satisfactorily describe the entire spectrum of interactions from strong chemical bonds to weak van der Waals forces. In this work, employing Pauli energy as the theoretical foundation, we fill in that knowledge gap. Our results show that the newly established density-based index can describe single and multiple covalent bonds, ionic bonds, metallic bonds, and different kinds of noncovalent interactions, all with unique and readily identifiable signature shapes. Two new descriptors, NBI (nonbonding and bonding identification) index and USI (ultra-strong interaction) index, have been introduced in this work. Together with NCI (noncovalent interaction) and SCI (strong covalent interaction) indexes already available in the literature, a density-based description of both chemical bonds and noncovalent interactions is accomplished.

Insight into Enzymatic Degradation of Physically Crosslinked Hydrogels Anchored by Functionalized Carbon Nanofillers

The effect of different geometries of functional carbon nanofillers has been studied to understand the nature of enzymatic degradation of physically crosslinked hydrogels. The noncovalent interactions between polymer and fillers...

Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.

Variable-Temperature Native Mass Spectrometry for Studies of Protein Folding, Stabilities, Assembly, and Molecular Interactions

The structures and conformational dynamics of proteins, protein complexes, and their noncovalent interactions with other molecules are controlled specifically by the Gibbs free energy (entropy and enthalpy) of the system. For some organisms, temperature is highly regulated, but the majority of biophysical studies are carried out at room, nonphysiological temperature. In this review, we describe variable-temperature electrospray ionization (vT-ESI) mass spectrometry (MS)-based studies with unparalleled sensitivity, dynamic range, and selectivity for studies of both cold- and heat-induced chemical processes. Such studies provide direct determinations of stabilities, reactivities, and thermodynamic measurements for native and non-native structures of proteins and protein complexes and for protein–ligand interactions. Highlighted in this review are vT-ESI-MS studies that reveal 40 different conformers of chymotrypsin inhibitor 2, a classic two-state (native → unfolded) unfolder, and thermochemistry for a model membrane protein system binding lipid and its regulatory protein. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.