To elucidate the consequences of the saturated-unsaturated nature of lipid surface films, monolayers formed by an equimolar mixture of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipids are investigated in a wide range of surface pressures. As such mixtures share some features with naturally-occurring surfactants, for example the lung surfactant, the systems are studied at the temperature relevant for human body. All-atom molecular dynamics simulations and Langmuir trough experiments are employed. The binary lipid mixture is compared with the corresponding one-component systems. Atomistic-level alterations of monolayer molecular properties upon lateral compression are scrutinized. These involve elevation of lateral ordering of lipid chains, modulation of chain and headgroup orientation, and reduction of lipid hydration. The presence of the unsaturated POPC in the DPPC/POPC mixture reduces the liquid expanded-liquid condensed coexistence region and moderates the phase transition. Simulations predict that nanoscale lipid de-mixing occurs with small transient DPPC clusters emerging due to local fluctuations of the lateral lipid arrangement. A vertical sorting of lipids induced by lateral compression is also observed, with DPPC transferred toward the water phase. Both the conformational lipid alterations due to monolayer compression as well as the existence of lateral dynamic inhomogeneities of the lipid film are potentially pertain to dynamic and non-homogeneous lipid interfacial systems.

• Klíčová slova
• Langmuir trough, Lung surfactant, Molecular dynamics, Phospholipid monolayers,
• MeSH
• 1,2-dipalmitoylfosfatidylcholin analogy a deriváty   chemie   MeSH
• fosfatidylcholiny chemie   MeSH
• lipidy chemie   MeSH
• molekulární konformace MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine MeSH Prohlížeč
• 1,2-dipalmitoylfosfatidylcholin MeSH
• 1,2-oleoylphosphatidylcholine MeSH Prohlížeč
• fosfatidylcholiny MeSH
• lipidy MeSH

We systematically investigate the applicability of a molecular dynamics-based setup for the calculations of standard binding free energies of biologically relevant protein-DNA complexes. The free energies are extracted from a potential of mean force calculated using umbrella sampling simulations. Two protein-DNA systems derived from a homeodomain transcription factor complex are studied in order to investigate the binding of both disordered and globular proteins. Free energies and trajectories obtained using two modern molecular mechanical force fields are compared to each other and to experimental data. The temperature dependence of the calculated standard binding free energies is investigated by performing all simulations over a range of temperatures. We show that the values of standard binding free energies obtained from these simulations are overestimated compared to experimental results. Significant differences are observed between the two protein-DNA systems and between the two force fields, which are explained by different propensities to form inter- and intramolecular contacts. The number of protein-DNA contacts increases with increasing temperature, in agreement with the experimentally known temperature dependence of enthalpies of binding. However, conclusions about the temperature dependence of the standard binding free energies cannot be made with confidence, as the differences among the values are on the order of statistical uncertainty.

• MeSH
• DNA chemie   metabolismus   MeSH
• entropie MeSH
• homeoboxový protein Nkx-2.5 chemie   metabolismus   MeSH
• homeodoménové proteiny chemie   metabolismus   MeSH
• lidé MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• teplota MeSH
• termodynamika * MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA MeSH
• homeoboxový protein Nkx-2.5 MeSH
• homeodoménové proteiny MeSH
• NKX2-5 protein, human MeSH Prohlížeč

All-atom molecular dynamics simulations are powerful tools for studying cell membranes and their interactions with proteins and other molecules. However, these processes occur on time scales determined by the diffusion rate of phospholipids, which are challenging to achieve in all-atom models. Here, we present a new all-atom model that accelerates lipid diffusion by splitting phospholipid molecules into head and tail groups. The bilayer structure is maintained by using external lateral potentials, which compensate for the lipid split. This split model enhances lateral lipid diffusion more than ten times, allowing faster and cheaper equilibration of large systems with different phospholipid types. The current model has been tested on membranes containing PSM, POPC, POPS, POPE, POPA, and cholesterol. We have also evaluated the interaction of the split model membranes with the Disheveled DEP domain and amphiphilic helix motif of the transcriptional repressor Opi1 as representative of peripheral proteins as well as the dimeric fragment of the epidermal growth factor receptor transmembrane domain and the Human A2A Adenosine of G protein-coupled receptors as representative of transmembrane proteins. The split model can predict the interaction sites of proteins and their preferred phospholipid type. Thus, the model could be used to identify lipid binding sites and equilibrate large membranes at an affordable computational cost.

• MeSH
• buněčná membrána * chemie   metabolismus   MeSH
• difuze MeSH
• fosfolipidy * chemie   metabolismus   MeSH
• lidé MeSH
• lipidové dvojvrstvy * chemie   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fosfolipidy * MeSH
• lipidové dvojvrstvy * MeSH

In an effort to delineate how cholesterol protects membrane structure under oxidative stress conditions, we monitored the changes to the structure of lipid bilayers comprising 30 mol% cholesterol and an increasing concentration of Class B oxidized 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) glycerophospholipids, namely, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PoxnoPC), and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC), using atomistic molecular dynamics simulations. Increasing the content of oxidized phospholipids (oxPLs) from 0 to 60 mol% oxPL resulted in a characteristic reduction in bilayer thickness and increase in area per lipid, thereby increasing the exposure of the membrane hydrophobic region to water. However, cholesterol was observed to help reduce water injury by moving into the bilayer core and forming more hydrogen bonds with the oxPLs. Cholesterol also resists altering its tilt angle, helping to maintain membrane integrity. Water that enters the 1-nm-thick core region remains part of the bulk water on either side of the bilayer, with relatively few water molecules able to traverse through the bilayer. In cholesterol-rich membranes, the bilayer does not form pores at concentrations of 60 mol% oxPL as was shown in previous simulations in the absence of cholesterol.

• Klíčová slova
• Cholesterol protection, Lipid oxidation, Oxidative stress, Oxidized membranes, Pore formation,
• MeSH
• cholesterol chemie   metabolismus   MeSH
• fosfatidylcholiny chemie   metabolismus   MeSH
• fosfolipidy chemie   metabolismus   MeSH
• fosforylcholin analogy a deriváty   chemie   metabolismus   MeSH
• lipidové dvojvrstvy chemie   metabolismus   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine MeSH Prohlížeč
• 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Prohlížeč
• cholesterol MeSH
• fosfatidylcholiny MeSH
• fosfolipidy MeSH
• fosforylcholin MeSH
• lipidové dvojvrstvy MeSH

We employed all-atom MD simulations to investigate the impact of palmitoylation on the PAG transmembrane peptide within various lipid environments, including the less explored boundary region separating lipid-ordered (Lo) and lipid-disordered (Ld) membrane phases. We found that palmitoylation of the peptide reduces its impact on membrane thickness, particularly within the Lo and boundary environments. Despite their hydrophobic nature, the palmitoyl chains on the peptide did not significantly affect the hydration of the surrounding membrane. Interestingly, the boundary membrane environment was found to be especially compatible with the palmitoylated peptide, suggesting its potential for accumulation in phase boundaries. Our findings highlight the importance of understanding how palmitoylation-modified peptides behave within membranes, with crucial implications for cell signaling and membrane organization. This knowledge may also inform the optimization of lipid membrane-based drug delivery systems, by improving our understanding of how drugs and excipients can be most effectively arranged within these carriers.

• Klíčová slova
• Lipid membrane phases, MD simulations, Membranes, PAG, Palmitoylation,
• MeSH
• lipidové dvojvrstvy * chemie   MeSH
• lipoylace MeSH
• peptidy metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• lipidové dvojvrstvy * MeSH
• peptidy MeSH

Understanding the molecular mechanisms of pore formation is crucial for elucidating fundamental biological processes and developing therapeutic strategies, such as the design of drug delivery systems and antimicrobial agents. Although experimental methods can provide valuable information, they often lack the temporal and spatial resolution necessary to fully capture the dynamic stages of pore formation. In this study, we present two novel collective variables (CVs) designed to characterize membrane pore behavior, particularly its energetics, through molecular dynamics (MD) simulations. The first CV─termed Full-Path─effectively tracks both the nucleation and expansion phases of pore formation. The second CV─called Rapid─is tailored to accurately assess pore expansion in the limit of large pores, providing quick and reliable method for evaluating membrane line tension under various conditions. Our results clearly demonstrate that the line tension predictions from both our CVs are in excellent agreement. Moreover, these predictions align qualitatively with available experimental data. Specifically, they reflect higher line tension of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) lipids compared to pure POPC, the decrease in line tension of POPC vesicles as the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) content increases, and higher line tension when ionic concentration is increased. Notably, these experimental trends are accurately captured only by the all-atom CHARMM36 and prosECCo75 force fields. In contrast, the all-atom Slipids force field, along with the coarse-grained Martini 2.2, Martini 2.2 polarizable, and Martini 3 models, show varying degrees of agreement with experiments. Our developed CVs can be adapted to various MD simulation engines for studying pore formation, with potential implications in membrane biophysics. They are also applicable to simulations involving external agents, offering an efficient alternative to existing methodologies.

• MeSH
• buněčná membrána * chemie   metabolismus   MeSH
• fosfatidylcholiny chemie   MeSH
• lipidové dvojvrstvy * chemie   MeSH
• poréznost MeSH
• simulace molekulární dynamiky * MeSH
• termodynamika * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Prohlížeč
• fosfatidylcholiny MeSH
• lipidové dvojvrstvy * MeSH

We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-d-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 µs of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the "clamshell" motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD-TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine.

• Klíčová slova
• NMDA receptor transition, glutamate receptor gating, molecular dynamics simulations, molecular modeling, open and closed state,
• MeSH
• krysa rodu Rattus MeSH
• receptory N-methyl-D-aspartátu chemie   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu MeSH

In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔGbind) obtained for the Tam16 lead molecule was of -51.43 kcal/mol. When comparing this result with the ΔGbind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC50 = 0.19 μM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.

• Klíčová slova
• CNPq, National Council for Scientific and Technological Development, CoA, coenzyme A, FAS, fatty acid synthase, GAFF, general amber force field, GB, generalized born, HB, hydrogen bonds, INH, isoniazid, KatG, catalase-peroxidase, MD, molecular dynamics, MDR, multi-drug resistant, MM/GBSA, molecular mechanics/generalized-born surface area, NAD, nicotinamide adenine dinucleotide, NS, nanoseconds, PCA, acyl carrier protein, Pks13, Pks13, polyketide synthase 13, RESP, restrained electrostatic potential, RMSD, root mean square deviation, RMSF, root mean square fluctuations, TB, tuberculosis, TE, C-terminal thioesterase, XDR, extensively drug resistant, benzofuran, free energy, inhibitors, molecular dynamics, Δ internal energy, Δ, Van Der Waals contributions, Δ, electrostatic contribution, Δ, electrostatic contributions, Δ, energy of desolvation, Δ, energy of the molecular mechanics, Δ, non-polar contributions, Δ, polar contributions, Δ, polar solvation contribution,
• MeSH
• aminokyseliny MeSH
• antituberkulotika chemie   farmakologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   chemie   MeSH
• benzofurany chemie   farmakologie   MeSH
• konformace proteinů MeSH
• molekulární struktura MeSH
• objevování léků MeSH
• polyketidsynthasy antagonisté a inhibitory   chemie   MeSH
• simulace molekulární dynamiky * MeSH
• simulace molekulového dockingu * MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vodíková vazba MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminokyseliny MeSH
• antituberkulotika MeSH
• bakteriální proteiny MeSH
• benzofuran MeSH Prohlížeč
• benzofurany MeSH
• polyketide synthase Pks13, Mycobacterium tuberculosis MeSH Prohlížeč
• polyketidsynthasy MeSH

Carbon dots (CDs), one of the youngest members of the carbon nanostructure family, are now widely experimentally studied for their tunable fluorescence properties, bleaching resistance, and biocompatibility. Their interaction with biomolecular systems has also been explored experimentally. However, many atomistic details still remain unresolved. Molecular dynamics (MD) simulations enabling atomistic and femtosecond resolutions simultaneously are a well-established tool of computational chemistry which can provide useful insights into investigated systems. Here we present a full procedure for performing MD simulations of CDs. We developed a builder for generating CDs of a desired size and with various oxygen-containing surface functional groups. Further, we analyzed the behavior of various CDs differing in size, surface functional groups, and degrees of functionalization by MD simulations. These simulations showed that surface functionalized CDs are stable in a water environment through the formation of an extensive hydrogen bonding network. We also analyzed the internal dynamics of individual layers of CDs and evaluated the role of surface functional groups on CD stability. We observed that carboxyl groups interconnected the neighboring layers and decreased the rate of internal rotations. Further, we monitored changes in the CD shape caused by an excess of charged carboxyl groups or carbonyl groups. In addition to simulations in water, we analyzed the behavior of CDs in the organic solvent DMF, which decreased the stability of pure CDs but increased the level of interlayer hydrogen bonding. We believe that the developed protocol, builder, and parameters will facilitate future studies addressing various aspects of structural features of CDs and nanocomposites containing CDs.

• Publikační typ
• časopisecké články MeSH

G-quadruplexes (G4s) are non-canonical nucleic acid structures that fold through complex processes. Characterization of the G4 folding landscape may help to elucidate biological roles of G4s but is challenging both experimentally and computationally. Here, we achieved complete folding of a three-quartet parallel DNA G4 with (GGGA)3GGG sequence using all-atom explicit-solvent enhanced-sampling molecular dynamics (MD) simulations. The simulations suggested early formation of guanine stacks in the G-tracts, which behave as semi-rigid blocks in the folding process. The folding continues via the formation of a collapsed compact coil-like ensemble. Structuring of the G4 from the coil then proceeds via various cross-like, hairpin, slip-stranded and two-quartet ensembles and can bypass the G-triplex structure. Folding of the parallel G4 does not appear to involve any salient intermediates and is a multi-pathway process. We also carried out an extended set of simulations of parallel G-hairpins. While parallel G-hairpins are extremely unstable when isolated, they are more stable inside the coil structure. On the methodology side, we show that the AMBER DNA force field predicts the folded G4 to be less stable than the unfolded ensemble, uncovering substantial force-field issues. Overall, we provide unique atomistic insights into the folding landscape of parallel-stranded G4 but also reveal limitations of current state-of-the-art MD techniques.

• Klíčová slova
• Folding, G-Quadruplex, Molecular dynamics,
• MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• konformace nukleové kyseliny MeSH
• nukleové kyseliny * MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA MeSH
• nukleové kyseliny * MeSH