G-Protein Coupled Receptor-Ligand Dissociation Rates and Mechanisms from τRAMD Simulations

There is a growing appreciation of the importance of drug-target binding kinetics for lead optimization. For G protein-coupled receptors (GPCRs), which mediate signaling over a wide range of timescales, the drug dissociation rate is often a better predictor of in vivo efficacy than binding affinity, although it is more challenging to compute. Here, we assess the ability of the τ-Random Acceleration Molecular Dynamics (τRAMD) approach to reproduce relative residence times and reveal dissociation mechanisms and the effects of allosteric modulation for two important membrane-embedded drug targets: the β2-adrenergic receptor and the muscarinic acetylcholine receptor M2. The dissociation mechanisms observed in the relatively short RAMD simulations (in which molecular dynamics (MD) simulations are performed using an additional force with an adaptively assigned random orientation applied to the ligand) are in general agreement with much more computationally intensive conventional MD and metadynamics simulations. Remarkably, although decreasing the magnitude of the random force generally reduces the number of egress routes observed, the ranking of ligands by dissociation rate is hardly affected and agrees well with experiment. The simulations also reproduce changes in residence time due to allosteric modulation and reveal associated changes in ligand dissociation pathways.

Structural identification of N-glycan isomers using logically derived sequence tandem mass spectrometry

N-linked glycosylation is one of the most important protein post-translational modifications. Despite the importance of N-glycans, the structural determination of N-glycan isomers remains challenging. Here we develop a mass spectrometry method, logically derived sequence tandem mass spectrometry (LODES/MSn), to determine the structures of N-glycan isomers that cannot be determined using conventional mass spectrometry. In LODES/MSn, the sequences of successive collision-induced dissociation are derived from carbohydrate dissociation mechanisms and apply to N-glycans in an ion trap for structural determination. We validate LODES/MSn using synthesized N-glycans and subsequently applied this method to N-glycans extracted from soybean, ovalbumin, and IgY. Our method does not require permethylation, reduction, and labeling of N-glycans, or the mass spectrum databases of oligosaccharides and N-glycan standards. Moreover, it can be applied to all types of N-glycans (high-mannose, hybrid, and complex), as well as the N-glycans degraded from larger N-glycans by any enzyme or acid hydrolysis.

The influence of the methionine residue on the dissociation mechanisms of photoionized methionine-enkephalin probed by VUV action spectroscopy

VUV action spectroscopy has recently gained interest for the study of peptides and proteins. However, numerous aspects of the fundamental processes involved in the photodissociation are yet to be understood. It can, for example, be expected that sulfur-containing amino-acid residues have a significant impact on the dissociation processes following photoionization because of their potential involvement in the transport of electron holes in proteins. In order to investigate the influence of the sulfur-containing methionine residue on the VUV photodissociation of a small peptide a VUV action spectroscopy study of gas-phase protonated methionine-enkephalin and leucine-enkephalin in the photon energy range of 6–35 eV was performed. The results show that upon non-ionizing photoexcitation, the fragmentation patterns of the two peptides are nearly identical, whereas significant differences were observed upon photoionization. The differences between the fragment yields and the identified specific dissociation channels for methionine-enkephalin could be explained by the high electron hole affinity of sulfur, which efficiently directs the radical to the methionine side chain. Additionally, for both peptides the presence of the intact photoionized precursor ions was confirmed by their isotopic patterns and the stability of these species could be evaluated. Graphic abstract

The desalting/salting pathway: a route to form metastable aggregates with tuneable morphologies and lifetimes

We investigate the formation/re-dissociation mechanisms of hybrid complexes made from negatively charged PAA2k coated γ-Fe2O3 nanoparticles (NP) and positively charged polycations (PDADMAC) in aqueous solution in the regime of very...

Photodissociation of the methyl radical: The role of nonadiabatic couplings in enhancing the variety of dissociation mechanisms

The nonadiabatic photodissociation dynamics of the CH$_3$ (and CD$_3$) radical from the 3p$_z$ and 3s Rydberg states is investigated by applying a one-dimensional (1D) wave packet model that uses recently...

The effect of strain on water dissociation on reduced rutile TiO2(110) surface

The tensile strain along [11̄0] on the reduced TiO2(110) surface can greatly promote the dissociation of water, the compressive strain along [001] and [11̄0] can change the dissociation mechanisms.

Dissociation mechanism from highly charged bromophenol: ab initio molecular dynamics simulations

Dissociation mechanisms are studied by ab initio molecular dynamics simulations based on density functional theory for the highly charged bromophenol (C6H4OHBr)n+ (n ≤ 10) in the ground electronic state and in an electronic state which has a high electronic temperature Te characterized by Fermi–Dirac distribution. In the case of the ground state, the dissociation occurs through a sequential multi-stage process. At times shorter than 20 fs after the molecule is charged, hydrogens are dissociated from the molecule and, subsequently, the carbon ring breaks at about 150 fs In the case of an electronic state with high Te, the mechanism changes from a sequential dissociation process to a simultaneous process occurring at Te > 5 eV. To estimate the charge transfer time in a molecular bromide parent ion with +6 charge, which is generated through Auger cascades, we also performed nonadiabatic quantum-mechanical molecular dynamics (NAQMD) simulations that include the effects of nonadiabatic electronic transition with a surface-hopping approach.