A coarse‐grained model for disordered and multi‐domain proteins

Protein Science, Journal Year: 2024, Volume and Issue: 33(11)

Published: Oct. 16, 2024

Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C

Language: Английский

---

GōMartini 3: From large conformational changes in proteins to environmental bias corrections

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 16, 2024

ABSTRACT Coarse-grained modeling has become an important tool to supplement experimental measurements, allowing access spatio-temporal scales beyond all-atom based approaches. The GōMartini model combines structure- and physics-based coarse-grained approaches, balancing computational efficiency accurate representation of protein dynamics with the capabilities studying proteins in different biological environments. This paper introduces enhanced model, which a virtual-site implementation Gō models Martini 3. been extensively tested by community since release new version Martini. work demonstrates diverse case studies, ranging from protein-membrane binding protein-ligand interactions AFM force profile calculations. is also versatile, as it can address recent inaccuracies reported model. Lastly, discusses advantages, limitations, future perspectives 3 its combination models.

Language: Английский

---

Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Lipid-mediated delivery of active pharmaceutical ingredients (API) opened new possibilities in advanced therapies. By encapsulating an API into a lipid nanocarrier (LNC), one can safely deliver APIs not soluble water, those with otherwise strong adverse effects, or very fragile ones such as nucleic acids. However, for the rational design LNCs, detailed understanding composition-structure-function relationships is missing. This review presents currently available computational methods LNC investigation, screening, and design. The state-of-the-art physics-based approaches are described, focus on molecular dynamics simulations all-atom coarse-grained resolution. Their strengths weaknesses discussed, highlighting aspects necessary obtaining reliable results simulations. Furthermore, machine learning, i.e., data-based approach to lipid-mediated introduced. data produced by experimental theoretical provide valuable insights. Processing these help optimize LNCs better performance. In final section this Review, computer reviewed, specifically addressing compatibility

Language: Английский

---

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

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 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.

Language: Английский

---

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, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 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.

Language: Английский

---

Assessing the Martini 3 protein model: A review of its path and potential

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2024, Volume and Issue: 1872(4), P. 141014 - 141014

Published: April 25, 2024

Language: Английский

---

A coarse-grained model for disordered and multi-domain proteins

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 7, 2024

Abstract Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C α atoms. also centre mass residue, obtain good agreement between simulations experiments across wide range then optimize our previously described CALVADOS using this centre-of-mass representation, validate resulting independent data. Finally, use revised simulate phase separation disordered proteins, examine stability differ dilute dense phases. Our results provide starting point understanding regions these affect propensity self-associate undergo separation.

Language: Английский

---

Implementation of Time-Averaged Restraints with UNRES Coarse-Grained Model of Polypeptide Chains

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Time-averaged restraints from nuclear magnetic resonance (NMR) measurements have been implemented in the UNRES coarse-grained model of polypeptide chains order to develop a tool for data-assisted modeling conformational ensembles multistate proteins, intrinsically disordered proteins (IDPs) and with regions (IDRs), many which are essential cell biology. A numerically stable variant molecular dynamics time-averaged has introduced, total energy is conserved sections trajectory microcanonical runs, bath temperature maintained canonical time-average-restraint-force components scaled up length memory window so that affect simulated structures. The new approach restores used generate ensemble-averaged distances, as demonstrated synthetic restraints. results better fitting interproton distances those determined experimentally regions, puts it at an advantage over all-atom approaches regard determination diffuse structures, owing faster more robust search.

Language: Английский

---

Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(2), P. 302 - 321

Published: Feb. 11, 2025

Biomolecular condensates composed of highly charged biomolecules, such as DNA, RNA, chromatin, and nucleic-acid binding proteins, are ubiquitous in the cell nucleus. The biophysical properties these charge-rich largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent ions implicitly widely used to gain mechanistic insights into condensates, offering transferability, computational efficiency, accurate predictions for multiple systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged, a residue-resolution model improves description charge effects biomolecular containing disordered multidomain and/or single-stranded RNAs. Mpipi-Recharged introduces pair-specific asymmetric Yukawa potential, informed atomistic simulations. We show this coarse-graining forces captures intricate effects, blockiness, stoichiometry variations complex coacervates, modulation salt concentration, without requiring explicit solvation. provides excellent agreement with experiments predicting phase behavior condensates. Overall, tools available investigate physicochemical mechanisms regulating enhancing scope computer simulations field.

Language: Английский

---

UNRES web server: extensions to nucleic acids, prediction of peptide aggregation, and new types of restrained calculations

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168968 - 168968

Published: Jan. 1, 2025

Language: Английский

---