Martini3-IDP: improved Martini 3 force field for disordered proteins

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 24, 2025

Coarse-grained (CG) molecular dynamics (MD) is widely used for the efficient simulation of intrinsically disordered proteins (IDPs). The Martini model, one most popular CG force fields in biomolecular simulation, was reported to yield too compact IDP conformations, limiting its applications. Addressing this, we optimized bonded parameters based on fitting reference simulations a diverse set IDPs at atomistic resolution, resulting Martini3-based protein model coined Martini3-IDP. This leads expanded greatly improving reproduction experimentally measured radii gyration. Moreover, contrary ad-hoc fixes scaling protein-protein or protein-water interactions, Martini3-IDP keeps overall interaction balance underlying 3. To validate that, perform comprehensive testing including full-length multidomain proteins, IDP-lipid membrane binding and IDP-small molecule binding, confirming ability successfully capture complex interplay between components. Finally, recently emerging concept condensate, through liquid-liquid phase separation, also reproduced by number both homotypic heterotypic systems. With improved expand simulate processes involving environments, spatio-temporal scales inaccessible with all-atom models. Here, authors introduce Martini3-IDP, refined that addresses prior over-compact structures. Validated across systems, it captures interactions condensates.

Язык: Английский

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OLIVES: A Go̅-like Model for Stabilizing Protein Structure via Hydrogen Bonding Native Contacts in the Martini 3 Coarse-Grained Force Field

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер unknown

Опубликована: Сен. 5, 2024

Coarse-grained molecular dynamics simulations enable the modeling of increasingly complex systems at millisecond timescales. The transferable coarse-grained force field Martini 3 has shown great promise in a wide range biochemical processes, yet folded proteins are not stable without application external bias potentials, such as elastic networks or Go̅-like models. We herein develop an algorithm, called OLIVES, which identifies native contacts with hydrogen bond capabilities and use it to implement novel model for 3. show that protein structure instability originates part from lack energy representation. By using realistic energies obtained literature ab initio calculations, is demonstrated stability can be recovered by reintroduction network OLIVES removes need secondary restraints. validated against known complexes same time addresses open question whether there quaternary simulations. It reduce number terms, hereby speeding up ≈30% on GPU architecture compared established Go̅MARTINI model.

Язык: Английский

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Recalibration of MARTINI-3 Parameters for Improved Interactions between Peripheral Proteins and Lipid Bilayers

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер 20(21), С. 9673 - 9686

Опубликована: Ноя. 4, 2024

The MARTINI force field is one of the most used coarse-grained models for biomolecular simulations. Many limitations model including protein-protein overaggregation have been improved in its latest version, MARTINI-3. In this study, we investigate efficacy MARTINI-3 parameters capturing interactions peripheral proteins with plasma membranes. Particularly, consider two classes proteins, namely, annexin and epsin, which are known to generate negative positive membrane curvatures, respectively. We find that current not able correctly describe protein-membrane interface protein-induced curvatures any these proteins. problem arises due lack proper hydrophobic between protein residues lipid tails. Making systematic adjustments, show a combination reduction protein-water enhancement protein-lipid essential accurate prediction interfacial structure curvature. Next, apply our couple other Snf7, core component ESCRT-III complex, PH domain evectin-2. captures much more accurately than all considered study. However, strategy described study may be suitable oligomeric transmembrane where should increased instead interactions.

Язык: Английский

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Plant protein–lipid interfaces studied by molecular dynamics simulations

Journal of Experimental Botany, Год журнала: 2024, Номер 75(17), С. 5237 - 5250

Опубликована: Май 16, 2024

Abstract The delineation of protein–lipid interfaces is essential for understanding the mechanisms various membrane-associated processes crucial to plant development and growth, including signalling, trafficking, membrane transport. Due their highly dynamic nature, precise characterization lipid–protein interactions by experimental techniques challenging. Molecular dynamics simulations provide a powerful computational alternative with spatial–temporal resolution allowing atomistic-level description. In this review, we aim introduce scientists molecular simulations. We describe different steps performing broad survey studies investigating interfaces. Our also illustrate that combining artificial intelligence-based protein structure determination opens up unprecedented possibilities future investigations

Язык: Английский

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Exploring the kinetics and mechanism of phase separation in ternary lipid mixtures containing APP C99 using atomistic vs coarse-grained MD simulations

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Abstract The phase separation of lipid bilayers, composed mixtures saturated and unsaturated lipids cholesterol, is a topic fundamental importance in membrane biophysics cell biology. formation domains, including liquid-disordered domains enriched liquid-ordered cholesterol believed to be essential the function many proteins. Experiment, theory, simulation have been used develop general understanding thermodynamic driving forces underlying ternary quaternary mixtures. However, kinetics early events presence transmembrane proteins remain relatively understudied. Using large-scale all-atom coarse-grained simulations, we explore lipid, cholesterol. Order parameters employed Cahn-Hilliard theory provide insight into mechanism separation. We observe three distinct time regimes process: shorter exponential followed by power law longer plateau phase. Comparison protein lipid-protein dynamics between models identifies both quantitative qualitative differences similarities kinetics. Moreover, timescaling AA CG yields similar kinetic findings this study elucidate aspects ongoing efforts define role rafts structure cellular membrane.

Язык: Английский

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Benchmark of Coacervate Formation and Mechanism Exploration Using the Martini Force Field

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Peptide-based coacervates are crucial for drug delivery due to their biocompatibility, versatility, high loading capacity, and cell penetration rates; however, stability mechanism phase behavior not fully understood. Additionally, although Martini is one of the most famous force fields capable describing coacervate formation with molecular details, a comprehensive benchmark its accuracy has been conducted. This research utilized 3.0 field machine learning algorithms explore representative peptide-based coacervates, including those composed polyaspartate (PAsp)/polyarginine (PArg), rmfp-1, sticker-and-spacer small molecules, HBpep molecules. We identified key driving forces such as Coulomb, cation–π, π–π interactions established three criteria determining in simulations. The results also indicate that while accurately captures trends, it tends underestimate Coulomb overestimate interactions. What more, our study on encapsulation derivative suggested loaded drugs were distributed surfaces clusters, awaiting experimental validation. employs simulation enhance understanding mechanisms benchmarking 3.0, thereby providing fundamental insights future investigations.

Язык: Английский

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Optimized Protein–Excipient Interactions in the Martini 3 Force Field

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

The high doses of drugs required for biotherapeutics, such as monoclonal antibodies (mAbs), and the small volumes that can be administered to patients by subcutaneous injections pose challenges due high-concentration formulations. addition excipients, arginine glutamate, protein formulations increase solubility reduce tendency particle formation. Molecular dynamics (MD) simulations provide microscopic insights into mode action excipients in mAb but require large system sizes long time scales are currently beyond reach at fully atomistic level. Computationally efficient coarse-grained models Martini 3 force field tackle this challenge careful parametrization, testing, validation. This study extends popular toward realistic protein–excipient interactions glutamate using Fab domains therapeutic mAbs trastuzumab omalizumab model systems. A novel all-atom mapping amino acid is introduced, which explicitly captures zwitterionic character backbone. Fab–excipient characterized concerning molecular contacts with Fabs single-residue compared results from a reference. Our findings reveal an overestimation default interaction parameters 3, suggesting too strong attraction between residues excipients. Therefore, we reparametrized against simulations. excipient obtained new Lennard-Jones (LJ) parameters, coined 3-exc, agree closely reference data. work presents improved parameter set mAb-arginine mAb-glutamate field, key step large-scale MD stabilizing effects

Язык: Английский

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Kinetics and Mechanism of Phase Separation in Ternary Lipid Mixtures Containing APP C99: Atomistic vs Coarse-Grained MD Simulations

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

The phase separation of lipid bilayers, composed mixtures saturated and unsaturated lipids cholesterol, is a topic fundamental importance in membrane biophysics cell biology. formation domains, including liquid-disordered domains enriched liquid-ordered believed to be essential the function many proteins. Experiment, theory, simulation have been used develop general understanding thermodynamic driving forces underlying ternary quaternary mixtures. However, kinetics early events presence transmembrane proteins remain relatively understudied. Using large-scale all-atom coarse-grained simulations, we explore lipid, cholesterol Order parameters employed Cahn-Hilliard theory provide insight into mechanism separation. We observe three distinct time regimes process: shorter exponential phase, followed by power-law then longer plateau phase. Comparison protein, lipid-protein dynamics between models identifies both quantitative qualitative differences similarities kinetics. Moreover, timescaling AA CG simulations yields similar kinetic findings this study elucidate aspects contribute ongoing efforts define role rafts structure cellular membrane.

Язык: Английский

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Two cooperative lipid binding sites within the pleckstrin homology domain are necessary for AKT binding and stabilization to the plasma membrane

Structure, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Highlights•A second PIP binding site was identified in the AKT PH domain•Both sites are necessary for a stable orientation of membrane•Mutation either stops membrane localization and phosphorylationSummaryAlmost four decades after identification protein understanding its role cancer, barriers remain translation inhibitors clinical applications. Here, we provide new molecular insight into first step activation where binds to plasma is stabilized bilayer with lateral heterogeneity (Lo-Ld phase coexistence). We have applied dynamic simulations cell biology approaches, demonstrate that recruitment requires pleckstrin homology (PH) domain acts cooperatively known canonical site. Given precision which protein-lipid interactions, study offers directions AKT-targeted therapy testing small molecules target these specific amino acid-PIP bonds.Graphical abstract

Язык: Английский

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From experimental studies to computational approaches: recent trends in designing novel therapeutics for amyloidogenesis

Journal of Materials Chemistry B, Год журнала: 2024, Номер unknown

Опубликована: Дек. 12, 2024

This review highlights the integration of various experimental and computational methods to control amyloid aggregation process. We believe that this article will help researchers develop novel therapeutic influence protein aggregation.

Язык: Английский

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