Emerging Era of Biomolecular Membrane Simulations: Automated Physically-Justified Force Field Development and Quality-Evaluated Databanks

Peer reviewe

Charged Small Molecule Binding to Membranes in MD Simulations Evaluated against NMR Experiments

Interactions of charged molecules with biomembranes regulate many of their biological activities, but their binding affinities to lipid bilayers are difficult to measure experimentally and model theoretically. Classical molecular dynamics (MD) simulations have the potential to capture the complex interactions determining how charged biomolecules interact with membranes, but systematic overbinding of sodium and calcium cations in standard MD simulations raises the question of how accurately force fields capture the interactions between lipid membranes and charged biomolecules. Here, we evaluate the binding of positively charged small molecules, etidocaine, and tetraphenylphosphonium to a phosphatidylcholine (POPC) lipid bilayer using the changes in lipid head-group order parameters. We observed that these molecules behave oppositely to calcium and sodium ions when binding to membranes: (i) their binding affinities are not overestimated by standard force field parameters, (ii) implicit inclusion of electronic polarizability increases their binding affinity, and (iii) they penetrate into the hydrophobic membrane core. Our results can be explained by distinct binding mechanisms of charged small molecules with hydrophobic moieties and monoatomic ions. The binding of the former is driven by hydrophobic effects, while the latter has direct electrostatic interactions with lipids. In addition to elucidating how different kinds of charged biomolecules bind to membranes, we deliver tools for further development of MD simulation parameters and methodology.Peer reviewe

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

Atomistic model for nearly quantitative simulations of Langmuir monolayers

Lung surfactant and a tear film lipid layer are examples of biologically relevant macromolecular structures found at the air–water interface. Because of their complexity, they are often studied in terms of simplified lipid layers, the simplest example being a Langmuir monolayer. Given the profound biological significance of these lipid assemblies, there is a need to understand their structure and dynamics on the nanoscale, yet there are not many techniques able to provide this information. Atomistic molecular dynamics simulations would be a tool fit for this purpose; however, the simulation models suggested until now have been qualitative instead of quantitative. This limitation has mainly stemmed from the challenge to correctly describe the surface tension of water with simulation parameters compatible with other biomolecules. In this work, we show that this limitation can be overcome by using the recently introduced four-point OPC water model, whose surface tension for water is demonstrated to be quantitatively consistent with experimental data and which is also shown to be compatible with the commonly employed lipid models. We further establish that the approach of combining the OPC four-point water model with the CHARMM36 lipid force field provides nearly quantitative agreement with experiments for the surface pressure–area isotherm for POPC and DPPC monolayers, also including the experimentally observed phase coexistence in a DPPC monolayer. The simulation models reported in this work pave the way for nearly quantitative atomistic studies of lipid-rich biological structures at air–water interfaces.Peer reviewe

Interfacial Tension and Surface Pressure of High Density Lipoprotein, Low Density Lipoprotein, and Related Lipid Droplets

AbstractLipid droplets play a central role in energy storage and metabolism on a cellular scale. Their core is comprised of hydrophobic lipids covered by a surface region consisting of amphiphilic lipids and proteins. For example, high and low density lipoproteins (HDL and LDL, respectively) are essentially lipid droplets surrounded by specific proteins, their main function being to transport cholesterol. Interfacial tension and surface pressure of these particles are of great interest because they are related to the shape and the stability of the droplets and to protein adsorption at the interface. Here we use coarse-grained molecular-dynamics simulations to consider a number of related issues by calculating the interfacial tension in protein-free lipid droplets, and in HDL and LDL particles mimicking physiological conditions. First, our results suggest that the curvature dependence of interfacial tension becomes significant for particles with a radius of ∼5 nm, when the area per molecule in the surface region is <1.4 nm2. Further, interfacial tensions in the used HDL and LDL models are essentially unaffected by single apo-proteins at the surface. Finally, interfacial tensions of lipoproteins are higher than in thermodynamically stable droplets, suggesting that HDL and LDL are kinetically trapped into a metastable state

Calcium Sensing by Recoverin : Effect of Protein Conformation on Ion Affinity

The detailed functional mechanism of recoverin, which acts as a myristoyl switch at the rod outer-segment disk membrane, is elucidated by direct and replica-exchange molecular dynamics. In accord with NMR structural evidence and calcium binding assays, simulations point to the key role of enhanced calcium binding to the EF3 loop of the semiopen state of recoverin as compared to the closed state. This 2-4-order decrease in calcium dissociation constant stabilizes the semiopen state in response to the increase of cytosolic calcium concentration in the vicinity of recoverin. A second calcium ion then binds to the EF2 loop and, consequently, the structure of the protein changes from the semiopen to the open state. The latter has the myristoyl chain extruded to the cytosol, ready to act as a membrane anchor of recoverin.Peer reviewe

Ahmakannan kehitys ja ahmakanta Suomessa 2020

Vuoden 2020 helmikuussa ahmoja oli 385–390 yksilöä, joista eleli poronhoitoalueella 135–140 ahmaa ja poronhoitoalueen ulkopuolella todennäköisimmin 249 yksilöä. Suomen ahmakannan yksilömäärä on kasvanut 1990-luvun alkupuoleen verrattuna noin kymmenkertaiseksi. Kanta on runsastunut keskimäärin noin 10 % vuodessa. Ykslömäärän kasvu on ollut viimeksi kuluneiden kymmenen vuoden aikana aiempaa voimakkaampaa. Arvio ahmakannasta ja sen kehityksestä pohjautuu riistakolmiolaskentoihin ja kolmen pohjoisimman kunnan (Enontekiö, Inari, Utsjoki) osalta Metsähallituksen koordinoimiin ja yhdessä paliskuntien kanssa suorittamiin aluelaskentoihin vuosina 2019–2020. Näin meneteltiin, koska kolmen pohjoisimman kunnan ahmat keskittyvät tunturialueella, missä on riistakolmioita erittäin vähän. Ahman ylitysjälkien määrä on asteittain kasvanut viime vuosina myös poronhoitoalueen riistakolmiolla, mutta Tunturi-Lapin aluelaskennoissa ahmoja todettiin selvästi vähemmän kuin vuosina 2013–2014.202

Ahmakanta Suomessa 2022

Vuoden 2022 helmikuussa ahmoja oli arviolta 390–410 yksilöä, joista liikkui poronhoitoalueella 160–180 ahmaa ja poronhoitoalueen ulkopuolella todennäköisimmin noin 230 yksilöä. Suomen ahmakannan yksilömäärä on kasvanut 1990-luvun alkuun verrattuna noin kymmenkertaiseksi. Riistakolmioilla laji runsastui vuosijaksolla 1990–2022 keskimäärin 8,9 % vuodessa. Vuoden 2022 kanta-arvio on hieman suurempi kuin vuoden 2021 arvio (390-400 ahmaa.) Yksilömäärän kasvu on ollut viimeksi kuluneiden kymmenen vuoden aikana aiempaa voimakkaampaa. Arvio ahmakannasta ja sen kehityksestä pohjautuu riistakolmiolaskentoihin ja kolmen pohjoisimman kunnan (Enontekiö, Inari, Utsjoki) osalta Metsähallituksen koordinoimiin ja yhdessä paliskuntien kanssa suorittamiin aluelaskentoihin vuosina 2020–2022. Näin meneteltiin, koska kolmen pohjoisimman kunnan ahmat keskittyvät tunturialueella, missä on riistakolmioita vähän. Ahman ylitysjälkien määrä on asteittain kasvanut viime vuosina myös poronhoitoalueen riistakolmiolla, mutta Tunturi-Lapin aluelaskennoissa todettujen ahmojen kokonaismäärässä ei ole ollut viime vuosina merkittäviä muutoksia. Ahmojen määrä oli siellä selvästi nykyistä suurempi vuosina 2013–2014

Ahmakanta Suomessa 2023

Vuoden 2023 helmikuussa ahmojen lukumäärä Suomessa oli 447 (95 % todennäköisyysväli 390–504). Arvio pohjautuu riistakolmiolaskentoihin ja kolmen pohjoisimman kunnan (Enontekiö, Inari, Utsjoki) osalta Metsähallituksen koordinoimiin ja yhdessä paliskuntien kanssa suorittamiin aluelaskentoihin vuosina 2020–2023. Arvion pohjana on ahmojen todennäköisin yksilömäärä riistakolmioilla (407 yks., 95 %:n todennäköisyysväli 355–472 ahmaa) ja arvioon pohjoisimpien kuntien ahmakannasta (40 yks. 95 %:n todennäköisyysväli 35–45). Poronhoitoalueen riistakolmioilla liikkui 95 %:n todennäköisyydellä 114–193 ahmaa, todennäköisimmän yksilömäärän ollessa 146. Suomen ahmakannan yksilömäärä on kasvanut 1990-luvun alkuun verrattuna noin kymmenkertaiseksi. Riistakolmioilla laji runsastui vuosijaksolla 1990–2023 keskimäärin 9,0 % vuodessa. Vuoden 2023 kanta-arvio on 10 % suurempi kuin vuoden 2022 arvio (400 ahmaa). Yksilömäärän kasvu on ollut viimeksi kuluneiden kymmenen vuoden aikana aiempaa voimakkaampaa. Ahman ylitysjälkien määrä on asteittain kasvanut viime vuosina myös poronhoitoalueen riistakolmiolla, mutta Tunturi-Lapin aluelaskennoissa todettujen ahmojen kokonaismäärässä ei ole ollut viime vuosina merkittäviä muutoksia. Ahmojen määrä oli siellä nykyistä suurempi vuosina 2013–2014

Using Open Data to Rapidly Benchmark Biomolecular Simulations : Phospholipid Conformational Dynamics

Molecular dynamics (MD) simulations are widely used to monitor time-resolved motions of biomacromolecules, although it often remains unknown how closely the conformational dynamics correspond to those occurring in real life. Here, we used a large set of open-access MD trajectories of phosphatidylcholine (PC) lipid bilayers to benchmark the conformational dynamics in several contemporary MD models (force fields) against nuclear magnetic resonance (NMR) data available in the literature: effective correlation times and spin-lattice relaxation rates. We found none of the tested MD models to fully reproduce the conformational dynamics. That said, the dynamics in CHARMM36 and Slipids are more realistic than in the Amber Lipid14, OPLS-based MacRog, and GROMOS-based Berger force fields, whose sampling of the glycerol backbone conformations is too slow. The performance of CHARMM36 persists when cholesterol is added to the bilayer, and when the hydration level is reduced. However, for conformational dynamics of the PC headgroup, both with and without cholesterol, Slipids provides the most realistic description because CHARMM36 overestimates the relative weight of similar to 1 ns processes in the headgroup dynamics. We stress that not a single new simulation was run for the present work. This demonstrates the worth of open-access MD trajectory databanks for the indispensable step of any serious MD study: benchmarking the available force fields. We believe this proof of principle will inspire other novel applications of MD trajectory databanks and thus aid in developing biomolecular MD simulations into a true computational microscope-not only for lipid membranes but for all biomacromolecular systems.Peer reviewe