Constant pH molecular dynamics (CpHMD) has emerged as a powerful method for simulating pH-dependent processes in proteins and other biomolecules. The original implementation of the PME-based CpHMD in the GROMACS software included the CHARMM36 and Martini ...

With the convergence of data, computing power, and new methods, computational biology is at its most exciting moment. At PSI, we're asking the leading researchers in the field to discover where we're ...

Membrane proteins play a vital role in numerous cellular processes, including ion transport, intercellular communication, and antibiotic resistance. Ensuring their accurate orientation within lipid bi...

Nature Communications - The asymmetric distribution of lipopolysaccharide (LPS) on the surface of the bacterial outer membrane is essential and crucial for antibiotic resistance. Here, authors...

The asymmetric distribution of lipopolysaccharide (LPS) on the surface of the bacterial outer membrane is essential and crucial for antibiotic resistance. Here, authors characterize the LPS translocon...

Static protein structures can capture the association of lipids, but it is unclear whether the association is due to lipids acting as long-lived ligands or the solvation of preferred lipids around the protein. A computational-experimental framework has now shown that for the protein CLC-ec1, it is the change in lipid solvation energies that drives dimerization, with preferred lipids around the protein modulating this driving force.

The GW4 BioMed MRC Doctoral Training Partnership is a collaboration between Bath, Bristol, Cardiff and Exeter Universities.

ParametrizANI - Fast, Accurate and Free Dihedral Parametrization in the Cloud with TorchANI - palermolab/ParametrizANI

Lipid membranes are central to cellular life. Complementing experiments, computational modeling has been essential in unraveling complex lipid-biomolecule interactions, crucial in both academia and industry. The Martini model, a coarse-grained force field for efficient molecular dynamics simulations, is widely used to study membrane phenomena but has faced limitations, particularly in capturing realistic lipid phase behavior. Here, we present refined Martini 3 lipid models with a mapping scheme that distinguishes lipid tails that differ by just two carbon atoms, enhancing the structural resolution and thermodynamic accuracy of model membrane systems including ternary mixtures. The expanded Martini lipid library includes thousands of models, enabling simulations of complex and biologically relevant systems. These advancements establish Martini as a robust platform for lipid-based simulations across diverse fields.

Structural biology has had an increasing and pervasive role in drug discovery over the past 50 years – providing a molecular understanding of the mechanism underlying the activity of a biological syst...

Nature Communications - This study reveals that an outer membrane protein from the predator Bdellovibrio bacteriovorus forms a pentameric assembly that traps a lipid monolayer within. This allows...

Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A2A adenosine receptor ligands and solve their crystal stru...

The emergence of multidrug-resistant bacteria poses a significant threat to public health. Particularly, they are becoming increasingly resistant to β-lactam antibiotics, which are one of the most important drug classes for the treatment of bacterial infections. Ceftazidime-avibactam has shown promising activity against highly drug-resistant bacteria, including carbapenem-resistant Enterobacterales. However, an Ala294-Pro295 deletion in the Class CE. cloacaeAmpC β-lactamase can confer reduced susceptibility to these agents. In this study, we investigated the molecular mechanisms underlying the enhanced hydrolysis of ceftazidime by E. cloacae Ent385 AmpC β-lactamase with the deletion using quantum mechanics/molecular mechanics (QM/MM) simulations. We used constant pH molecular dynamics simulations of the β-lactamase-ceftazidime acyl-enzyme complex to verify the likely protonation states, confirming Tyr150 primarily exists as a tyrosinate. We then used QM/MM (DFTB2/ff14SB) umbrella sampling to calculate the reaction-free energy barriers (Δ‡G) for the deacylation step of cephalosporin hydrolysis. This reveals that Tyr150 (rather than the substrate) acts as the base. Importantly, the difference in Δ‡G between the canonical E. cloacae AmpC (P99) and the Ent385 variant with Ala294-Pro295 reinserted, on the one hand, and the Ent385 variant, on the other, was in very good agreement with the difference deduced from experimental kinetic data. Detailed analysis of the transition state ensembles, alongside additional simulations, shows that the Ala294-Pro295 deletion allows the entrance of an additional water molecule that helps stabilize the tetrahedral intermediate. Overall, our QM/MM simulations provide valuable insights into the reaction mechanism and reasons for enhanced ceftazidime breakdown. The protocol used in this study successfully captures the kinetic differences observed among the studied variants. This approach can be employed to investigate other Class C β-lactamase variants with similar features, providing insights into their mechanisms and potential contributions to reduced susceptibility to antibiotic treatments.