A Supervised Molecular Dynamics Approach to Unbiased Ligand–Protein Unbinding

The recent paradigm shift toward the use of the kinetics parameters in place of thermodynamic constants is leading the computational chemistry community to develop methods for studying the mechanisms of drug binding and unbinding. From this standpoint, molecular dynamics (MD) plays an important role in delivering insight at the molecular scale. However, a known limitation of MD is that the time scales are usually far from those involved in ligand–receptor unbinding events. Here, we show that the algorithm behind supervised MD (SuMD) can simulate the dissociation mechanism of druglike small molecules while avoiding the input of any energy bias to facilitate the transition. SuMD was tested on seven different intermolecular complexes, covering four G protein-coupled receptors: the A2A and A1 adenosine receptors, the orexin 2 and the muscarinic 2 receptors, and the soluble globular enzyme epoxide hydrolase. SuMD well-described the multistep nature of ligand–receptor dissociation, rationalized previous experimental data and produced valuable working hypotheses for structure–kinetics relationships

Acoustic module of the Acquabona (Italy) debris flow monitoring system

International audienceMonitoring of debris flows aimed to the assessment of their physical parameters is very important both for theoretical and practical purposes. Peak discharge and total volume of debris flows are crucial for designing effective countermeasures in many populated mountain areas where losses of lives and property damage could be avoided. This study quantifies the relationship between flow depth, acoustic amplitude of debris flow induced ground vibrations and front velocity in the experimental catchment of Acquabona, Eastern Dolomites, Italy. The analysis of data brought about the results described in the following. Debris flow depth and amplitude of the flow-induced ground vibrations show a good positive correlation. Estimation of both mean front velocity and peak discharge can be simply obtained monitoring the ground vibrations, through geophones installed close to the flow channel; the total volume of debris flow can be so directly estimated from the integral of the ground vibrations using a regression line. The application of acoustic technique to debris flow monitoring seems to be of the outmost relevance in risk reduction policies and in the correct management of the territory. Moreover this estimation is possible in other catchments producing debris flows of similar characteristics by means of their acoustic characterisation through quick and simple field tests (Standard Penetration Tests and seismic refraction surveys)

Is the Stalk of the SARS-CoV-2 Spike Protein Druggable?

The spike protein is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain (RBD) encounter with ACE2. As targeting subunit S1 has not yet delivered an ACE2-binding inhibitor, we have assessed the druggability of the conserved segment of the spike protein stalk within subunit S2 by means of an integrated computational approach that combines the molecular docking of an optimized library of fragments with high-throughput molecular dynamics simulations. The high propensity of the spike protein to mutate in key regions that are responsible for the recognition of the human angiotensin-converting enzyme 2 (hACE2) or for the recognition of antibodies, has made subunit S1 of the spike protein difficult to target. Despite the inherent flexibility of the stalk region, our results suggest two hidden interhelical binding sites, whose accessibility is only partially hampered by glycan residues

Analysis of Mechanical Response during Folding of Creased and Uncreased Paperboard

Creasing and folding of paperboard are two essential operations to obtain a well-defined shape and strength of a package. Relative Crease Strength, RCS, is specified for process control of creasing and folding and is defined as the ratio between the maximal bending force for a crease and uncreased sample bend to the bending angle of 30 degrees at a rate of 5 degrees/sec. Thus, the present work had as objective to evaluate RCS measured in real industrial samples used for process control of creasing and evaluate the influence of paperboard properties and converting processes creasing and folding. As RCS can be measured only after creasing, the study can give directions to paperboard production process control. Creasing measurements were done on both machine direction (MD) and cross machine direction (CD) samples. The paperboard property that showed the highest correlation to RCS was Scott Bond. Based on this one pilot production with lower Scott Bond was evaluated. Lower values of RCS were obtained, as predicted. X-Ray microtomography revealed higher stratification between fiber layers in the paperboard with lower Scott Bond

A Pathway Model to Understand the Evolution of Spike Protein Binding to ACE2 in SARS-CoV-2 Variants

After the SARS-CoV-2 Wuhan variant that gave rise to the pandemic, other variants named Delta, Omicron, and Omicron-2 sequentially became prevalent, with mutations spread around the viral genome, including on the spike (S) protein; in order to understand the resultant in gains in infectivity, we interrogated in silico both the equilibrium binding and the binding pathway of the virus’ receptor-binding domain (RBD) to the angiotensin-converting enzyme 2 (ACE2) receptor. We interrogated the molecular recognition between the RBD of different variants and ACE2 through supervised molecular dynamics (SuMD) and classic molecular dynamics (MD) simulations to address the effect of mutations on the possible S protein binding pathways. Our results indicate that compensation between binding pathway efficiency and stability of the complex exists for the Omicron BA.1 receptor binding domain, while Omicron BA.2′s mutations putatively improved the dynamic recognition of the ACE2 receptor, suggesting an evolutionary advantage over the previous strains

Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity

Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.

Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.Leverhulme Trus