Evaluating Polarizable Biomembrane Simulations against Experiments.

Owing to the increase of available computational capabilities and the potential for providing a more accurate description, polarizable molecular dynamics force fields are gaining popularity in modeling biomolecular systems. It is, however, crucial to evaluate how much precision is truly gained with increasing cost and complexity of the simulation. Here, we leverage the NMRlipids open collaboration and Databank to assess the performance of available polarizable lipid models─the CHARMM-Drude and the AMOEBA-based parameters─against high-fidelity experimental data and compare them to the top-performing nonpolarizable models.

Overlay databank unlocks data-driven analyses of biomolecules for all.

Tools based on artificial intelligence (AI) are currently revolutionising many fields, yet their applications are often limited by the lack of suitable training data in programmatically accessible format. Here we propose an effective solution to make data scattered in various locations and formats accessible for data-driven and machine learning applications using the overlay databank format. To demonstrate the practical relevance of such approach, we present the NMRlipids Databank-a community-driven, open-for-all database featuring programmatic access to quality-evaluated atom-resolution molecular dynamics simulations of cellular membranes.

Effects of ion type and concentration on the structure and aggregation of the amyloid peptide A .

Among the various factors controlling the amyloid aggregation process, the influences of ions on the aggregation rate and the resulting structures are important aspects to consider, which can be studied by molecular simulations. There is a wide variety of protein force fields and ion models, raising the question of which model to use in such studies. To address this question, we perform molecular dynamics simulations of Aβ , a fragment of the Alzheimer's amyloid β peptide, using different protein force fields, AMBER99SB-disp (A99-d) and CHARMM36m (C36m), and different ion parameters.

Measuring pico-Newton Forces with Lipid Anchors as Force Sensors in Molecular Dynamics Simulations.

Binding forces between biomolecules are ubiquitous in nature but sometimes as weak as a few pico-Newtons (pN). In many cases, the binding partners are attached to biomembranes with the help of a lipid anchor. One important example are glycolipids that promote membrane adhesion through weak carbohydrate-carbohydrate binding between adjacent membranes.

Does the inclusion of electronic polarisability lead to a better modelling of peptide aggregation?

Simulating the process of amyloid aggregation with atomic detail is a challenging task for various reasons. One of them is that it is difficult to parametrise a force field such that all protein states ranging from the folded through the unfolded to the aggregated state are represented with the same level of accuracy. Here, we test whether the consideration of electronic polarisability improves the description of the different states of Aβ.

Probing the Link between Pancratistatin and Mitochondrial Apoptosis through Changes in the Membrane Dynamics on the Nanoscale.

Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity toward cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent.

Interplay of - and -Interactions of Glycolipids in Membrane Adhesion.

Glycolipids mediate stable membrane adhesion of potential biological relevance. In this article, we investigate the - and -interactions of glycolipids in molecular dynamics simulations and relate these interactions to the glycolipid-induced average separations of membranes obtained from neutron scattering experiments. We find that the -interactions between glycolipids in the same membrane leaflet tend to strengthen the -interactions between glycolipids in apposing leaflets.

Disorder-to-order transition of the amyloid-β peptide upon lipid binding.

There is mounting evidence that Alzheimer's disease progression and severity are linked to neuronal membrane damage caused by aggregates of the amyloid-β (Aβ) peptide. However, the detailed mechanism behind the membrane damage is not well understood yet. Recently, the lipid-chaperone hypothesis has been put forward, based on which the formation of complexes between Aβ and free lipids enables an easy insertion of Aβ into membranes.

Different Force Fields Give Rise to Different Amyloid Aggregation Pathways in Molecular Dynamics Simulations.

The progress toward understanding the molecular basis of Alzheimers's disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of Aβ into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field.

Weak carbohydrate-carbohydrate interactions in membrane adhesion are fuzzy and generic.

Carbohydrates such as the trisaccharide motif LeX are key constituents of cell surfaces. Despite intense research, the interactions between carbohydrates of apposing cells or membranes are not well understood. In this article, we investigate carbohydrate-carbohydrate interactions in membrane adhesion as well as in solution with extensive atomistic molecular dynamics simulations that exceed the simulation times of previous studies by orders of magnitude.

Headgroup Structure and Cation Binding in Phosphatidylserine Lipid Bilayers.

Phosphatidylserine (PS) is a negatively charged lipid type commonly found in eukaryotic membranes, where it interacts with proteins via nonspecific electrostatic interactions as well as via specific binding. Moreover, in the presence of calcium ions, PS lipids can induce membrane fusion and phase separation. Molecular details of these phenomena remain poorly understood, partly because accurate models to interpret the experimental data have not been available.

Function changing mutations in glucocorticoid receptor evolution correlate with their relevance to mode coupling.

Nonlinear effects in protein dynamics are expected to play role in function, particularly of allosteric nature, by facilitating energy transfer between vibrational modes. A recently proposed method focusing on the non-Gaussian shape of the configurational population near equilibrium projects this information onto real space in order to identify the aminoacids relevant to function. We here apply this method to three ancestral proteins in glucocorticoid receptor (GR) family and show that the mutations that restrict functional activity during GR evolution correlate significantly with locations that are highlighted by the nonlinear contribution to the near-native configurational distribution.

Force generation by the growth of amyloid aggregates.

The generation of mechanical forces are central to a wide range of vital biological processes, including the function of the cytoskeleton. Although the forces emerging from the polymerization of native proteins have been studied in detail, the potential for force generation by aberrant protein polymerization has not yet been explored. Here, we show that the growth of amyloid fibrils, archetypical aberrant protein polymers, is capable of unleashing mechanical forces on the piconewton scale for individual filaments.