Письма в Журнал экспериментальной и теоретической физики, Год журнала: 2024, Номер 119(7-8), С. 624 - 629
Опубликована: Сен. 25, 2024
Molecular Pharmaceutics, Год журнала: 2025, Номер unknown
Опубликована: Фев. 20, 2025
Permeability is an important molecular property in drug discovery, as it co-determines pharmacokinetics whenever a crosses the phospholipid bilayer, e.g., into cell, gastrointestinal tract, or across blood-brain barrier. Many methods for determination of permeability have been developed, including cell line assays (CACO-2 and MDCK), cell-free model systems like parallel artificial membrane assay (PAMPA) mimicking, epithelia skin, well black lipid (BLM) submicrometer liposomes. Furthermore, many silico approaches developed prediction: meta-analysis publicly available databases data (MolMeDB ChEMBL) was performed to establish their usability. Four experimental two computational were evaluated. It shown that repeatability reported measurement not great even same method. For PAMPA method, different permeabilities are reported: intrinsic apparent. They can vary degrees magnitude; thus, we suggest being extra cautious using literature on permeability. When compared molecules methods, best agreement between cell-based BLM methods. Existence unstirred water layer (UWL) limits (and apparent PAMPA) with limited by UWL (computational BLM, PAMPA). Therefore, limitations. Cell-based provide results only small range (-8 -4 cm/s), predict wider beyond physical limitations, but precision therefore limited. liposomes be used both fast slow permeating molecules, its usage more complicated than standard transwell techniques. To sum up, when working in-house measured published data, recommend caution interpreting combining them.
Язык: Английский
Процитировано
1
Wiley Interdisciplinary Reviews Computational Molecular Science, Год журнала: 2024, Номер 14(1)
Опубликована: Янв. 1, 2024
Abstract Potassium (K + ) channels play vital roles in various physiological functions, including regulating K flow cell membranes, impacting nervous system signal transduction, neuronal firing, muscle contraction, neurotransmitters, and enzyme secretion. Their activation switch‐off are directly linked to diseases like arrhythmias, atrial fibrillation, pain etc. Although the experimental methods important studying structure function of channels, they still some limitations enclose dynamic molecular processes corresponding mechanisms conformational changes during ion transport, permeation, gating control. Relatively, computational have obvious advantages such problems compared with methods. Recently, more three‐dimensional structures been disclosed based on silico prediction methods, which provide a good chance study mechanism related functional regulations channels. Based these structural details, dynamics simulations together as enhanced sampling free energy calculations, widely used reveal dynamics, conductance, channel gating, ligand binding mechanisms. Additionally, accessibility also provides large space for structure‐based drug design. This review mainly addresses recent progress structure, mechanism, design After summarizing fields, we give our opinion future direction area research combined cutting edge article is categorized under: Molecular Statistical Mechanics > Dynamics Monte‐Carlo Methods Structure Mechanism Computational Biochemistry Biophysics Data Science Chemoinformatics
Язык: Английский
Процитировано
4
JETP Letters, Год журнала: 2024, Номер 119(8), С. 643 - 648
Опубликована: Апрель 1, 2024
Peripheral membrane proteins are temporarily coupled to the surface of a membrane, penetrating into lipid layer. In this work, it has been shown that fraction trans configurations dihedral angles in hydrophobic chains lipids decreases region contact peripheral with membrane. This effect differs for different and at distances from beginning chain. A gosh configuration higher energy than configuration. Consequently, decrease leads an increase The chain conformations protein considered work increases by ≈2 kJ/mol. is involved molecular mechanisms determining elastic modulus membranes. stored conformation can be spent desorption as reason why interaction temporal.
Язык: Английский
Процитировано
1
The Journal of Physical Chemistry B, Год журнала: 2024, Номер unknown
Опубликована: Июль 11, 2024
Curvature emerges as a fundamental membrane characteristic crucial for diverse biological processes, including vesicle formation, cell signaling, and trafficking. Increasingly valuable insights into atomistic details governing curvature-dependent properties are provided by computer simulations. Nevertheless, the underlying force field models conventionally calibrated tested in relation to experimentally derived parameters of planar bilayers, thereby leaving uncertainties concerning their consistency reproducing curved lipid systems. In this study we compare depiction buckled phosphatidylcholine (POPC) POPC–cholesterol membranes four popular models. Aside from agreement with respect general trends curvature dependence number parameters, observe few qualitative differences. Among most prominent ones is difference between coarse grained fields representation relative compressibility polar headgroup region hydrophobic core. Through downstream effects, discrepancy can influence way which modulates behavior bound proteins depending on adopted simulation model.
Язык: Английский
Процитировано
1
Опубликована: Авг. 30, 2024
Permeability is an important molecular property in drug discovery, as it co-determines pharmacokinetics whenever a crosses the phospholipid bilayer, e.g., into cell, gastrointestinal tract or across blood-brain barrier. Many methods for determination of permeability have been developed, including cell line assays, cell-free model systems like PAMPA mimicking, epithelia skin, well Black lipid membrane (BLM) and sub-micrometer liposomes. Furthermore, many silico approaches developed prediction. Meta-analysis publicly available databases data (MolMeDB ChEMBL) was performed to establish their usability. Firstly, experimental can only be measured between thresholds lowest highest permeation rate obtainable within physical boundaries. These vary strongly methods. Secondly, computed do not obey these but, on other hand, produce incorrect results. Thirdly, even same method molecule, there often strong discrepancy individual values. differences are based statistics but also varying evaluation data. Thus, when working with in-house published data, we recommend cautious interpretation.
Язык: Английский
Процитировано
1
The Journal of Physical Chemistry B, Год журнала: 2024, Номер 128(9), С. 2144 - 2153
Опубликована: Фев. 26, 2024
SNX proteins have been found to induce membrane remodeling facilitate the generation of transport carriers in endosomal pathways. However, molecular mechanism bending and role lipids process remain elusive. Here, we conducted coarse-grained dynamics simulations investigate three structural modules (PX, BAR, AH) SNX1 PI3P deformation. We observed that presence all domains is essential for achieve a stable BAR capable through charged residues on its concave surface, but it requires PX AH establish binding. penetrates into lipid membrane, thereby promoting induction curvature; however, inadequate own maintain bending. are also indispensable remodeling, as they play dominant interactions with domain. Our results enhance comprehension underlying SNX1-induced curvature help future studies curvature-inducing proteins.
Язык: Английский
Процитировано
0
KIMIKA, Год журнала: 2024, Номер 34(2), С. 61 - 86
Опубликована: Авг. 23, 2024
In addressing the global problem of antimicrobial resistance, an emerging class molecules called peptides (AMPs) are being widely studied. Their interactions with cell membranes instrumental in their killing action, usually by forming pores or translocating to act on internal target. Molecular dynamics (MD) simulations have played essential role understanding atomistic mechanisms such interactions. This review will highlight key findings from various MD studies, as formation nanoaggregates and different types pores. We also discuss selecting membrane model composition, level detail simulation, choice force field. It is evident this that our AMPs has grown over recent years through help simulations. Still, remaining concerns studies systems must be addressed gain more information.
Язык: Английский
Процитировано
0
Письма в Журнал экспериментальной и теоретической физики, Год журнала: 2024, Номер 119(7-8), С. 624 - 629
Опубликована: Сен. 25, 2024
Процитировано
0