Understanding Ring Puckering in Small Molecules and Cyclic Peptides

<div>The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, five- and six-membered carbohydrate rings and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer-Pople puckering coordinates to study the trends of the ring conformation across a set of 140,000 diverse small molecules, including small rings, macrocycles and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted, and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the interrelated changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low energy ring conformations for applications from polymeric materials to drug binding.</div>

Understanding Ring Puckering in Small Molecules and Cyclic Peptides

<div>The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, five- and six-membered carbohydrate rings and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer-Pople puckering coordinates to study the trends of the ring conformation across a set of 140,000 diverse small molecules, including small rings, macrocycles and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted, and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the interrelated changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low energy ring conformations for applications from polymeric materials to drug binding.</div>

A viral genome packaging motor transitions between cyclic and helical symmetry to translocate dsDNA

SUMMARYMolecular segregation and biopolymer manipulation require the action of molecular motors to do work by applying directional forces to macromolecules. The additional strand conserved E (ASCE) ring motors are an ancient family of molecular motors responsible for diverse tasks ranging from biological polymer manipulation (e.g. protein degradation and chromosome segregation) to establishing and maintaining proton gradients across mitochondrial membranes. Viruses also utilize ASCE segregation motors to package their genomes into their protein capsids and serve as accessible experimental systems due to their relative simplicity. We show by CryoEM focused image reconstruction that ASCE ATPases in viral dsDNA packaging motors adopt helical symmetry complementary to their dsDNA substrates. Together with previous data, including structural results showing these ATPases in planar ring conformations, our results suggest that these motors cycle between helical and planar cyclical symmetry, providing a possible mechanism for directional translocation of DNA. We further note that similar changes in quaternary structure have been observed for proteasome and helicase motors, suggesting an ancient and common mechanism of force generation that has been adapted for specific tasks over the course of evolution.

Conformational potential energy surfaces and cationic structure of 3,4-dihydro-2H-pyran by VUV-MATI spectroscopy and Franck–Condon fitting

Ring conformations of 3,4-dihydro-2H-pyran (34DHP) have attracted considerable interest owing to their structural similarity to cyclohexene, an important molecule in stereochemistry.

ATP hydrolysis-coupled peptide translocation mechanism of Mycobacterium tuberculosis ClpB

The protein disaggregase ClpB hexamer is conserved across evolution and has two AAA+-type nucleotide-binding domains, NBD1 and NBD2, in each protomer. In M. tuberculosis (Mtb), ClpB facilitates asymmetric distribution of protein aggregates during cell division to help the pathogen survive and persist within the host, but a mechanistic understanding has been lacking. Here we report cryo-EM structures at 3.8- to 3.9-Å resolution of Mtb ClpB bound to a model substrate, casein, in the presence of the weakly hydrolyzable ATP mimic adenosine 5′-[γ-thio]triphosphate. Mtb ClpB existed in solution in two closed-ring conformations, conformers 1 and 2. In both conformers, the 12 pore-loops on the 12 NTDs of the six protomers (P1–P6) were arranged similarly to a staircase around the bound peptide. Conformer 1 is a low-affinity state in which three of the 12 pore-loops (the protomer P1 NBD1 and NBD2 loops and the protomer P2 NBD1 loop) are not engaged with peptide. Conformer 2 is a high-affinity state because only one pore-loop (the protomer P2 NBD1 loop) is not engaged with the peptide. The resolution of the two conformations, along with their bound substrate peptides and nucleotides, enabled us to propose a nucleotide-driven peptide translocation mechanism of a bacterial ClpB that is largely consistent with several recent unfoldase structures, in particular with the eukaryotic Hsp104. However, whereas Hsp104’s two NBDs move in opposing directions during one step of peptide translocation, in Mtb ClpB the two NBDs move only in the direction of translocation.

Pyranose ring conformations in mono- and oligosaccharides: a combined MD and DFT approach

A two-step computational protocol is proposed to efficiently study the conformational properties of hexopyranoses with a special emphasis on their ring-inversion-properties. By applying it, the errors resulting from overestimating the contribution of the hydrogen bond-rich, low-energy structures that are not abundant in aqueous solutions are avoided.

Extension and validation of the GLYCAM force field parameters for modeling glycosaminoglycans

Glycosaminoglycans (GAGs) are an important class of carbohydrates that serve critical roles in blood clotting, tissue repair, cell migration and adhesion, and lubrication. The variable sulfation pattern and iduronate ring conformations in GAGs influence their polymeric structure and nature of interaction. This study characterizes several heparin-like GAG disaccharides and tetrasaccharides using NMR and molecular dynamics simulations to assist in the development of parameters for GAGs within the GLYCAM06 force field. The force field additions include parameters and charges for a transferable sulfate group for O- and N-sulfation, neutral (COOH) forms of iduronic and glucuronic acid, and Δ4,5-unsaturated uronate (ΔUA) residues. ΔUA residues frequently arise from the enzymatic digestion of heparin and heparin sulfate. Simulations of disaccharides containing ΔUA reveal that the presence of sulfation on this residue alters the relative populations of 1H2 and 2H1 ring conformations. Simulations of heparin tetrasaccharides containing N-sulfation in place of N-acetylation on glucosamine residues influence the ring conformations of adjacent iduronate residues.