Accurate Simulations of Lipid Monolayers Require a Water Model with Correct Surface Tension

Lipid monolayers provide our lungs and eyes their functionality and serve as proxy systems in biomembrane research. Therefore, lipid monolayers have been studied intensively including using molecular dynamics simulations, which are able to probe their lateral structure and interactions with, e.g., pharmaceuticals or nanoparticles. However, such simulations have struggled in describing the forces at the air-water interface. Particularly, the surface tension of water and long-range van der Waals interactions have been considered critical, but their importance in monolayer simulations has been evaluated only separately. Here, we combine the recent C36/LJ-PME lipid force field that includes long-range van der Waals forces with water models that reproduce experimental surface tensions to elucidate the importance of these contributions in monolayer simulations. Our results suggest that a water model with correct surface tension is necessary to reproduce experimental surface pressure-area isotherms and monolayer phase behavior. The latter includes the liquid expanded and liquid condensed phases, their coexistence, and the opening of pores at the correct area per lipid upon expansion. Despite these improvements of the C36/LJ-PME with certain water models, the standard cutoff-based CHARMM36 lipid model with the 4-point OPC water model still provides the best agreement with experiments. Our results emphasize the importance of using high-quality water models in applications and parameter development in molecular dynamics simulations of biomolecules.Peer reviewe

Ionic Strength and Solution Composition Dictate the Adsorption of Cell-Penetrating Peptides onto Phosphatidylcholine Membranes

Adsorption of arginine-rich positively charged peptides onto neutral zwitterionic phosphocholine (PC) bilayers is a key step in the translocation of those potent cell-penetrating peptides into the cell interior. In the past, we have shown both theoretically and experimentally that polyarginines adsorb to the neutral PC-supported lipid bilayers in contrast to polylysines. However, comparing our results with previous studies showed that the results often do not match even at the qualitative level. The adsorption of arginine-rich peptides onto 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) may qualitatively depend on the actual experimental conditions where binding experiments have been performed. In this work, we systematically studied the adsorption of R9 and K9 peptides onto the POPC bilayer, aided by molecular dynamics (MD) simulations and fluorescence cross-correlation spectroscopy (FCCS) experiments. Using MD simulations, we tested a series of increasing peptide concentrations, in parallel with increasing Na+ and Ca2+ salt concentrations, showing that the apparent strength of adsorption of R9 decreases upon the increase of peptide or salt concentration in the system. The key result from the simulations is that the salt concentrations used experimentally can alter the picture of peptide adsorption qualitatively. Using FCCS experiments with fluorescently labeled R9 and K9, we first demonstrated that the binding of R9 to POPC is tighter by almost 2 orders of magnitude compared to that of K9. Finally, upon the addition of an excess of either Na+ or Ca2+ ions with R9, the total fluorescence correlation signal is lost, which implies the unbinding of R9 from the PC bilayer, in agreement with our predictions from MD simulations.Peer reviewe

Developing biomolecular interactions models for molecular simulations: Critical evaluation of force field parametrizations

Force field molecular dynamics methods are nowadays commonly used to study molecular interactions in many scientific fields. The accuracy of force fields has been improving over the years, allowing for a meaningful physical description of molecular phenomena. However, force fields have limitations. In this dissertation, I explored some of these limitations resulting from the parametrization strategy of force fields and the extent to which non-classical behavior, such as nuclear quantum effects, can be incorporated into classical force field molecular dynamics. In the first part, I investigated to what extent nuclear quantum effects can be accounted for within a classical force field for water. This allowed us to model the differences between bulk light vs. heavy water. The developed model was then used to describe solvent isotope effects on biomolecules, such as amino acids, proteins, and biomembranes, and to seek an explanation why heavy water (unlike light water) tastes sweet. In the second part, I pointed out the drawbacks of using certain training datasets in comparison to others when optimizing a force field, using aqueous calcium chloride as an example. In the third part, I demonstrated the importance of using an accurate water model during the optimization of force fields for phospholipids to adequately capture..

Vývoj biomolekulových interakčních modelů pro molekulové simulace: kritická evaluace parametrizací silových polí

Force field molecular dynamics methods are nowadays commonly used to study molecular interactions in many scientific fields. The accuracy of force fields has been improving over the years, allowing for a meaningful physical description of molecular phenomena. However, force fields have limitations. In this dissertation, I explored some of these limitations resulting from the parametrization strategy of force fields and the extent to which non-classical behavior, such as nuclear quantum effects, can be incorporated into classical force field molecular dynamics. In the first part, I investigated to what extent nuclear quantum effects can be accounted for within a classical force field for water. This allowed us to model the differences between bulk light vs. heavy water. The developed model was then used to describe solvent isotope effects on biomolecules, such as amino acids, proteins, and biomembranes, and to seek an explanation why heavy water (unlike light water) tastes sweet. In the second part, I pointed out the drawbacks of using certain training datasets in comparison to others when optimizing a force field, using aqueous calcium chloride as an example. In the third part, I demonstrated the importance of using an accurate water model during the optimization of force fields for phospholipids to adequately capture...Metody molekulové dynamiky s použitím silových polí jsou dnes běžně používány ke studiu molekulových interakcí v mnoha vědeckých oblastech. Přesnost silových polí se v průběhu let zlepšovala, což umožnilo smysluplný fyzikální popis molekulových jevů. Nicméně, silová pole mají své omezení. V této disertaci jsem prozkoumával některá tato omezení, jež jsou důsledkem strategie parametrizace silových polí, a zjišťoval, do jaké míry lze do klasické molekulové dynamiky s použitím silových polí zahrnout neklasické chování jako jsou kvantové efekty spojené s pohyby jader. V první části jsem zkoumal, do jaké míry lze kvantové efekty jader zahrnout do klasického silového pole pro vodu. To nám umožnilo modelovat rozdíly mezi těžkou a lehkou vodou. Vyvinutý model byl poté použit k popisu izotopových efektů rozpouštědla na biomolekuly jako jsou aminokyseliny, proteiny a biomembrány, a k hledání vysvětlení proč těžká voda (na rozdíl od lehké vody) chutná sladce. Ve druhé části dizertace jsem upozornil na nevýhody použití určitých trénovacích datových sad při optimalizaci silového pole na příkladu chloridu vápenatého ve vodném roztoku. V třetí části jsem demonstroval důležitost použití přesného modelu vody během optimalizace silových polí pro fosfolipidy, aby bylo možné adekvátně zachytit chování lipidové vrstvy. Všechny...Katedra fyzikální a makromol. chemieDepartment of Physical and Macromolecular ChemistryFaculty of SciencePřírodovědecká fakult

Accurate Simulations of Lipid Monolayers Require a Water Model With Correct Surface Tension

Lipid monolayers provide our lungs and eyes their functionality, and serve as proxy systems in biomembrane research. Therefore, lipid monolayers have been studied intensively also using molecular dynamics simulations, which are able to probe their lateral structure and interactions with, e.g., pharmaceuticals or nanoparticles. However, such simulations have struggled in describing the forces at the air–water interface. Particularly the surface tension of water and long-range van der Waals interactions have been considered critical, but their importance in monolayer simulations has been evaluated only separately. Here we combine the recent C36/LJ-PME lipid force field that in- cludes long-range van der Waals forces with water models that reproduce experimental surface tensions to elucidate the importance of these contributions in monolayer simulations. Our results suggest that a water model with correct surface tension is necessary to reproduce experimental surface pressure–area isotherms and monolayer phase behavior, while standard cutoff-based CHARMM36 lipid model with the 4-point OPC water model still provides the best agreement with experiments. Our results emphasize the importance of using high quality water models in applications and parameter development in molecular dynamics simulations of biomolecules

A unifying framework for amyloid-mediated membrane damage: The lipid-chaperon hypothesis

Over the past thirty years, researchers have highlighted the role played by a class of proteins or polypeptides that forms pathogenic amyloid aggregates in vivo, including i) the amyloid Abeta peptide, which is known to form senile plaques in Alzheimer's disease; ii) alpha-synuclein, responsible for Lewy body formation in Parkinson's disease and iii) IAPP, which is the protein component of type 2 diabetes-associated islet amyloids. These proteins, known as intrinsically disordered proteins (IDPs), are present as highly dynamic conformational ensembles. IDPs can partially (mis) fold into (dys) functional conformations and accumulate as amyloid aggregates upon interaction with other cytosolic partners such as proteins or lipid membranes. In addition, an increasing number of reports link the toxicity of amyloid proteins to their harmful effects on membrane integrity. Still, the molecular mechanism underlying the amyloidogenic proteins transfer from the aqueous environment to the hydrocarbon core of the membrane is poorly understood. This review starts with a historical overview of the toxicity models of amyloidogenic proteins to contextualize the more recent lipid-chaperone hypothesis. Then, we report the early molecular-level events in the aggregation and ion-channel pore formation of Abeta, IAPP, and alpha-synuclein interacting with model membranes, emphasizing the complexity of these processes due to their different spatial-temporal resolutions. Next, we underline the need for a combined experimental and computational approach, focusing on the strengths and weaknesses of the most commonly used techniques. Finally, the last two chapters highlight the crucial role of lipid-protein complexes as molecular switches among ion-channel-like formation, detergent-like, and fibril formation mechanisms and their implication in fighting amyloidogenic diseases.Comment: 45 pages, 3 figure

Effects of Water Deuteration on Thermodynamic and Structural Properties of Proteins and Biomembranes

Light and heavy water are often used interchangeably in spectroscopic experiments with the tacit assumption that the structure of the investigated biomolecule does not depend too much on employing one or the other solvent. While this may often be a good approximation, we demonstrate here using molecular dynamics simulations incorporating nuclear quantum effects via modification of the interaction potential that there are small but significant differences. Namely, as quantified and discussed in the present study, both proteins and biomembranes tend to be slightly more compact and rigid in D2O than in H2O, which reflects the stronger hydrogen bonding in the former solvent

The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

Increasing number of human diseases have been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer’s, and Parkinson’s, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.</p

Exposure to Aldehyde Cherry e-Liquid Flavoring and Its Vaping Byproduct Disrupt Pulmonary Surfactant Biophysical Function

Over the past decade, there has been a significant rise in the use of vaping devices, particularly among adolescents, raising concerns for effects on respiratory health. Pressingly, many recent vaping-related lung injuries are unexplained by current knowledge, and the overall implications of vaping for respiratory health are poorly understood. This study investigates the effect of hydrophobic vaping liquid chemicals on the pulmonary surfactant biophysical function. We focus on the commonly used flavoring benzaldehyde and its vaping byproduct, benzaldehyde propylene glycol acetal. The study involves rigorous testing of the surfactant biophysical function in Langmuir trough and constrained sessile drop surfactometer experiments with both protein-free synthetic surfactant and hydrophobic protein-containing clinical surfactant models. The study reveals that exposure to these vaping chemicals significantly interferes with the synthetic and clinical surfactant biophysical function. Further atomistic simulations reveal preferential interactions with SP-B and SP-C surfactant proteins. Additionally, data show surfactant lipid-vaping chemical interactions and suggest significant transfer of vaping chemicals to the experimental subphase, indicating a toxicological mechanism for the alveolar epithelium. Our study, therefore, reveals novel mechanisms for the inhalational toxicity of vaping. This highlights the need to reassess the safety of vaping liquids for respiratory health, particularly the use of aldehyde chemicals as vaping flavorings.Peer reviewe

Exposure to Aldehyde Cherry e‑Liquid Flavoring and Its Vaping Byproduct Disrupt Pulmonary Surfactant Biophysical Function

Over the past decade, there has been a significant rise in the use of vaping devices, particularly among adolescents, raising concerns for effects on respiratory health. Pressingly, many recent vaping-related lung injuries are unexplained by current knowledge, and the overall implications of vaping for respiratory health are poorly understood. This study investigates the effect of hydrophobic vaping liquid chemicals on the pulmonary surfactant biophysical function. We focus on the commonly used flavoring benzaldehyde and its vaping byproduct, benzaldehyde propylene glycol acetal. The study involves rigorous testing of the surfactant biophysical function in Langmuir trough and constrained sessile drop surfactometer experiments with both protein-free synthetic surfactant and hydrophobic protein-containing clinical surfactant models. The study reveals that exposure to these vaping chemicals significantly interferes with the synthetic and clinical surfactant biophysical function. Further atomistic simulations reveal preferential interactions with SP-B and SP-C surfactant proteins. Additionally, data show surfactant lipid–vaping chemical interactions and suggest significant transfer of vaping chemicals to the experimental subphase, indicating a toxicological mechanism for the alveolar epithelium. Our study, therefore, reveals novel mechanisms for the inhalational toxicity of vaping. This highlights the need to reassess the safety of vaping liquids for respiratory health, particularly the use of aldehyde chemicals as vaping flavorings