Investigating How Lysophosphatidylcholine and Lysophosphatidylethanolamine Enhance the Membrane Permeabilization Efficacy of Host Defense Peptide Piscidin 1.

Lysophospholipids (LPLs) and host defense peptides (HDPs) are naturally occurring membrane-active agents that disrupt key membrane properties, including the hydrocarbon thickness, intrinsic curvature, and molecular packing. Although the membrane activity of these agents has been widely examined separately, their combined effects are largely unexplored. Here, we use experimental and computational tools to investigate how lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), an LPL of lower positive spontaneous curvature, influence the membrane activity of piscidin 1 (P1), an α-helical HDP from fish.

CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published.

Simulating asymmetric membranes using P2 periodic boundary conditions.

Molecular dynamics (MD) simulations of symmetric lipid bilayers are now well established, while those of asymmetric ones are considerably less developed. This disjunction arises in part because the surface tensions of leaflets in asymmetric bilayers can differ (unlike those of symmetric ones), and there is no simple way to determine them without assumptions. This chapter describes the use of P2 periodic boundary conditions (PBC), which allow lipids to switch leaflets, to generate asymmetric bilayers under the assumption of equal chemical potentials of lipids in opposing leaflets.

Ion-Induced PIP2 Clustering with Martini3: Modification of Phosphate-Ion Interactions and Comparison with CHARMM36.

Phosphatidylinositol 4,5-bisphosphate (PIP) is a critical lipid for cellular signaling. The specific phosphorylation of the inositol ring controls protein binding as well as clustering behavior. Two popular models to describe ion-mediated clustering of PIP are Martini3 (M3) and CHARMM36 (C36).

Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.

Background: Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear.

Methods: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs.

Spontaneous curvature generation by peptides in asymmetric bilayers.

Peptides and proteins play crucial roles in membrane remodeling by inducing spontaneous curvature. However, extracting spontaneous curvatures from simulations of asymmetric bilayers is challenging because differential stress (i.e.

Flipped C-Terminal Ends of APOA1 Promote ABCA1-dependent Cholesterol Efflux by Small HDLs.

Background: Cholesterol efflux capacity (CEC) predicts cardiovascular disease (CVD) independently of HDL cholesterol (HDL-C) levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 pathway, but the underlying mechanisms are unclear.

Methods: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 in the different particles, and the CECs of plasma and isolated HDLs.

Short hydrocarbon stapled ApoC2-mimetic peptides activate lipoprotein lipase and lower plasma triglycerides in mice.

Introduction: Defects in lipolysis can lead to hypertriglyceridemia, which can trigger acute pancreatitis and is also associated with cardiovascular disease. Decreasing plasma triglycerides (TGs) by activating lipoprotein lipase (LPL) with ApoC2 mimetic peptides is a new treatment strategy for hypertriglyceridemia. We recently described a dual ApoC2 mimetic/ApoC3 antagonist peptide called D6PV that effectively lowered TG in several mouse models but has limitations in terms of drug development.

Unsaturated Lipids Facilitate Partitioning of Transmembrane Peptides into the Liquid Ordered Phase.

The affinity of single-pass transmembrane (TM) proteins for ordered membrane phases has been reported to depend on their lipidation, TM length, and lipid accessible surface area. In this work, the raft affinities of the TM domain of the linker for activation of T cells and its depalmitoylated variant are assessed using free energy simulations in a binary bilayer system composed of two laterally patched bilayers of ternary liquid ordered (Lo) and liquid disordered (Ld) phases. These phases are modeled by distinct compositions of distearoylphosphatidylcholine, palmitoyloleoylphosphatidylcholine (POPC), and cholesterol, and the simulations were carried out for 4.

Drude Polarizable Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Saturated and Monounsaturated Zwitterionic Lipids.

Accurate empirical force fields of lipid molecules are a critical component of molecular dynamics simulation studies aimed at investigating properties of monolayers, bilayers, micelles, vesicles, and liposomes, as well as heterogeneous systems, such as protein-membrane complexes, bacterial cell walls, and more. While the majority of lipid force field-based simulations have been performed using pairwise-additive nonpolarizable models, advances have been made in the development of the polarizable force field based on the classical Drude oscillator model. In the present study, we undertake further optimization of the Drude lipid force field, termed Drude2023, including improved treatment of the phosphate and glycerol linker region of PC and PE headgroups, additional optimization of the alkene group in monounsaturated lipids, and inclusion of long-range Lennard-Jones interactions using the particle-mesh Ewald method.

Surface viscosities of lipid bilayers determined from equilibrium molecular dynamics simulations.

Lipid membrane viscosity is critical to biological function. Bacterial cells grown in different environments alter their lipid composition in order to maintain a specific viscosity, and membrane viscosity has been linked to the rate of cellular respiration. To understand the factors that determine the viscosity of a membrane, we ran equilibrium all-atom simulations of single component lipid bilayers and calculated their viscosities.

Initiation and evolution of pores formed by influenza fusion peptides probed by lysolipid inclusion.

The fusion peptide (FP) domain is necessary for the fusogenic activity of spike proteins in a variety of enveloped viruses, allowing the virus to infect the host cell, and is the only part of the protein that interacts directly with the target membrane lipid tails during fusion. There are consistent findings of poration by this domain in experimental model membrane systems, and, in certain conditions, the isolated FPs can generate pores. Here, we use molecular dynamics simulations to investigate the specifics of how these FP-induced pores form in membranes with different compositions of lysolipid and POPC.

Planar aggregation of the influenza viral fusion peptide alters membrane structure and hydration, promoting poration.

To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out from the viral surface to embed into the target cellular membrane. Here we report that synthesized influenza virus FPs are membrane active, generating pores in giant unilamellar vesicles (GUV), and thus potentially explain both influenza virus' hemolytic activity and the liposome poration seen in cryo-electron tomography. Experimentally, FPs are heterogeneously distributed on the GUV at the time of poration.

Finite-Size Effects in Simulations of Peptide/Lipid Assembly.

Molecular dynamics simulations are an attractive tool for understanding lipid/peptide self-assembly but can be plagued by inaccuracies when the system sizes are too small. The general guidance from self-assembly simulations of homogeneous micelles is that the total number of surfactants should be three to five times greater than the equilibrium aggregate number of surfactants per micelle. Herein, the heuristic is tested on the more complicated self-assembly of lipids and amphipathic peptides using the Cooke and Martini 3 coarse-grained models.

Design principles of PI(4,5)P clustering under protein-free conditions: Specific cation effects and calcium-potassium synergy.

Phosphatidylinositol 4,5-bisphosphate (PIP2) clustering is a key component in cell signaling, yet little is known about the atomic-level features of this phenomenon. Network-theoretic analysis of multimicrosecond atomistic simulations of PIP2 containing asymmetric bilayers under protein-free conditions, presented here, reveals how design principles of PIP2 clustering are determined by the specific cation effects. Ca2+ generates large clusters (6% are pentamer or larger) by adding existing PIP2 dimers formed by strong O‒Ca2+‒O bridging interactions of unprotonated P4/P5 phosphates.

Developing initial conditions for simulations of asymmetric membranes: a practical recommendation.

It has been proposed that the surface tension difference between leaflets (or differential stress) in asymmetric bilayers is generally nonvanishing. This implies that there is no unique approach to generate initial conditions for simulations of asymmetric bilayers in the absence of experimentally derived constraints. Current generation methods include individual area per lipid (APL) based, leaflet surface area (SA) matching, and zero leaflet tension based (0-DS).

Development of CHARMM Additive Potential Energy Parameters for α-Methyl Amino Acids.

Potential energy parameters for α-methyl amino acids were generated with ab initio calculations on α-methyl--acetylalanyl-'-methylamide (the α-methyl "alanine dipeptide") which served as an input to a grid-based correction to the backbone torsional potential (known as CMAP) consistent with the CHARMM36m additive protein force field. The new parameters were validated by comparison with experimentally determined helicities of the 22 residue C-terminal peptide (H10) from apolipoprotein A1 and five α-methylated variants in water and 0.3:0.

Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation.

Small molecules such as metabolites and drugs must pass through the membrane of the cell, a barrier primarily comprising phospholipid bilayers and embedded proteins. To better understand the process of passive diffusion, knowledge of the ability of various functional groups to partition across bilayers and the associated energetics would be of utility. In the present study, the site identification by ligand competitive saturation (SILCS) methodology has been applied to sample the distributions of a diverse set of chemical solutes representing the functional groups of small molecules across phospholipid bilayers composed of 0.

Location and Conformational Ensemble of Menaquinone and Menaquinol, and Protein-Lipid Modulations in Archaeal Membranes.

Halobacteria, a type of archaea in high salt environments, have phytanyl ether phospholipid membranes containing up to 50% menaquinone. It is not understood why a high concentration of menaquinone is required and how it influences membrane properties. In this study, menaquinone-8 headgroup and torsion parameters of isoprenoid tail are optimized in the CHARMM36 force field.

Semi-automated Optimization of the CHARMM36 Lipid Force Field to Include Explicit Treatment of Long-Range Dispersion.

The development of the CHARMM lipid force field (FF) can be traced back to the early 1990s with its current version denoted CHARMM36 (C36). The parametrization of C36 utilized high-level quantum mechanical data and free energy calculations of model compounds before parameters were manually adjusted to yield agreement with experimental properties of lipid bilayers. While such manual fine-tuning of FF parameters is based on intuition and trial-and-error, automated methods can identify beneficial modifications of the parameters via their sensitivities and thereby guide the optimization process.

CHARMM36 Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Phosphatidylethanolamine, Phosphatidylglycerol, and Ether Lipids.

Long-range Lennard-Jones (LJ) interactions have been incorporated into the CHARMM36 (C36) lipid force field (FF) using the LJ particle-mesh Ewald (LJ-PME) method in order to remove the inconsistency of bilayer and monolayer properties arising from the exclusion of long-range dispersion [Yu, Y.; Semi-automated Optimization of the CHARMM36 Lipid Force Field to Include Explicit Treatment of Long-Range Dispersion. 2021, 10.

Membrane permeability of small molecules from unbiased molecular dynamics simulations.

Permeation of many small molecules through lipid bilayers can be directly observed in molecular dynamics simulations on the nano- and microsecond timescale. While unbiased simulations provide an unobstructed view of the permeation process, their feasibility for computing permeability coefficients depends on various factors that differ for each permeant. The present work studies three small molecules for which unbiased simulations of permeation are feasible within less than a microsecond, one hydrophobic (oxygen), one hydrophilic (water), and one amphiphilic (ethanol).

PLD2-PI(4,5)P2 interactions in fluid phase membranes: Structural modeling and molecular dynamics simulations.

Interaction of phospholipase D2 (PLD2) with phosphatidylinositol (4,5)-bisphosphate (PIP2) is regarded as the critical step of numerous physiological processes. Here we build a full-length model of human PLD2 (hPLD2) combining template-based and ab initio modeling techniques and use microsecond all-atom molecular dynamics (MD) simulations of the protein in contact with a complex membrane to determine hPLD2-PIP2 interactions. MD simulations reveal that the intermolecular interactions preferentially occur between specific PIP2 phosphate groups and hPLD2 residues; the most strongly interacting residues are arginine at the pbox consensus sequence (PX) and pleckstrin homology (PH) domain.