Lipid membranes are central to cellular life. Complementing experiments, computational modeling has been essential in unraveling complex lipid-biomolecule interactions, crucial in both academia and industry. The Martini model, a coarse-grained force field for efficient molecular dynamics simulations, is widely used to study membrane phenomena but has faced limitations, particularly in capturing realistic lipid phase behavior. Here, we present refined Martini 3 lipid models with a mapping scheme that distinguishes lipid tails differing by just two carbon atoms, enhancing structural resolution and thermodynamic accuracy of model membrane systems including ternary mixtures. The expanded Martini lipid library includes thousands of models, enabling simulations of complex and biologically relevant systems. These advancements establish Martini as a robust platform for lipid-based simulations across diverse fields.
Many antimicrobial peptides function by forming pores in the plasma membrane of the target cells. Intriguingly, some of these peptides are very short, and thus, it is not known how they can span the membrane, or whether other mechanisms of cell disruption are dominant. Here, the conformation and orientation of the 14-residue peptaibol SPF-5506-A4 (SPF) are investigated in lipid environments by atomistic and coarse grained molecular dynamics (MD) simulations, circular dichroism, and nuclear magnetic resonance (NMR) experiments. The MD simulations show that SPF is inserted spontaneously in a transmembrane orientation in both 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers resulting in thinning of the bilayers near the peptides, which drives the peptide aggregation. Furthermore, the backbone conformation of the peptide in the bilayer bound state is different from that of the NMR model solved in small bicelles. These results demonstrate that mutual adaption between the peptides and the membrane is likely to be important for pore formation.
Lipid nanoparticles (LNPs) represent a promising platform for advanced drug and gene delivery, yet optimizing these particles for specific cargos and cell targets poses a complex, multifaceted challenge. Furthermore, there is a pressing need for a more comprehensive understanding of the underlying technology. Experimental studies are costly and often provide low-resolution information. Molecular dynamics (MD) simulations allow us to study these particles at a higher resolution, enhancing our understanding. However, studying these systems at atomic resolutions is both challenging and computationally expensive, as well as time-consuming. Coarse-grained (CG) models, such as Martini 3, are positioned as promising tools for studying LNPs. To enable CG-MD studies of LNPs, accurate and validated models of their components are needed. Here, we present a substantial extension of the Martini 3 library of lipids, covering the most important LNP components, including over a hundred of ionizable lipid (IL) models, along with natural occurring sterol models and PEGylated lipid models. We furthermore present initial protocols for screening fusion efficacy across different lipid formulations and for constructing whole LNPs at CG resolution, enabling future studies of these nanoparticles.
Lipid nanoparticles (LNPs) represent a promising platform for advanced drug and gene delivery, yet optimizing these particles for specific cargos and cell targets poses a complex, multifaceted challenge. Furthermore, there is a pressing need for a more comprehensive understanding of the underlying technology. Experimental studies are costly and often provide low-resolution information. Molecular dynamics (MD) simulations allow us to study these particles at a higher resolution, enhancing our understanding. However, studying these systems at atomic resolutions is both challenging and computationally expensive, as well as time-consuming. Coarse-grained (CG) models, such as Martini 3, are positioned as promising tools for studying LNPs. To enable CG-MD studies of LNPs, accurate and validated models of their components are needed. Here, we present a substantial extension of the Martini 3 library of lipids, covering the most important LNP components, including over a hundred of ionizable lipid (IL) models, along with natural occurring sterol models and PEGylated lipid models. We furthermore present initial protocols for screening fusion efficacy across different lipid formulations and for constructing whole LNPs at CG resolution, enabling future studies of these nanoparticles.
Coarse-grained (CG) modelling with the Martini force field has come of age. By combining a variety of bead types and sizes with a new mapping approach, the newest version of the model is able to accurately simulate large biomolecular complexes at millisecond timescales. In this perspective, we discuss possible applications of the Martini 3 model in drug discovery and development pipelines and highlight areas for future development. Owing to its high simulation efficiency and extended chemical space, Martini 3 has great potential in the area of drug design and delivery. However, several aspects of the model should be improved before Martini 3 CG simulations can be routinely employed in academic and industrial settings. These include the development of automatic parameterisation protocols for a variety of molecule types, the improvement of backmapping procedures, the description of protein flexibility and the development of methodologies enabling efficient sampling. We illustrate our view with examples on key areas where Martini could give important contributions such as drugs targeting membrane proteins, cryptic pockets and protein–protein interactions and the development of soft drug delivery systems.
Secretory proteins are critically dependent on the correct processing of their signal sequence by the signal peptidase complex (SPC). This step, which is essential for the proper folding and localization of proteins in eukaryotic cells, is still not fully understood. In eukaryotes, the SPC comprises four evolutionarily conserved membrane subunits (Spc1-3 and Sec11). Here, we investigated the role of Spc2, examining SPC cleavage efficiency on various models and natural signal sequences in yeast cells depleted of or with mutations in Spc2. Our data show that discrimination between substrates and identification of the cleavage site by SPC is compromised when Spc2 is absent or mutated. Molecular dynamics simulation of the yeast SPC AlphaFold2-Multimer model indicates that membrane thinning at the center of SPC is reduced without Spc2, suggesting a molecular explanation for the altered substrate recognition properties of SPC lacking Spc2. These results provide new insights into the molecular mechanisms by which SPC governs protein biogenesis.
Coarse-grained (CG) modelling with the Martini force field has come of age. By combining a variety of bead types and sizes with a new mapping approach, the newest version of the model is able to accurately simulate large biomolecular complexes at millisecond timescales. In this perspective, we discuss possible applications of the Martini 3 model in drug discovery and development pipelines and highlight areas for future development. Owing to its high simulation efficiency and extended chemical space, Martini 3 has great potential in the area of drug design and delivery. However, several aspects of the model should be improved before Martini 3 CG simulations can be routinely employed in academic and industrial settings. These include the development of automatic parameterisation protocols for a variety of molecule types, the improvement of backmapping procedures, the description of protein flexibility and the development of methodologies enabling efficient sampling. We illustrate our view with examples on key areas where Martini could give important contributions such as drugs targeting membrane proteins, cryptic pockets and protein–protein interactions and the development of soft drug delivery systems.
Nanodiscs are membrane mimetics that consist of a protein belt surrounding a lipid bilayer, and are broadly used for characterization of membrane proteins. Here, we investigate the structure, dynamics and biophysical properties of two small nanodiscs, MSP1D1ΔH5 and ΔH4H5. We combine our SAXS and SANS experiments with molecular dynamics simulations and previously obtained NMR and EPR data to derive and validate a conformational ensemble that represents the structure and dynamics of the nanodisc. We find that it displays conformational heterogeneity with various elliptical shapes, and with substantial differences in lipid ordering in the centre and rim of the discs. Together, our results reconcile previous apparently conflicting observations about the shape of nanodiscs, and pave the way for future integrative studies of larger complex systems such as membrane proteins embedded in nanodiscs.
Coarse-grained (CG) modelling with the Martini force field has come of age. By combining a variety of bead types and sizes with a new mapping approach, the newest version of the model is able to accurately simulate large biomolecular complexes at millisecond timescales. In this perspective, we discuss possible applications of the Martini 3 model in drug discovery and development pipelines and highlight areas for future development. Owing to its high simulation efficiency and extended chemical space, Martini 3 has great potential in the area of drug design and delivery. However, several aspects of the model should be improved before Martini 3 CG simulations can be routinely employed in academic and industrial settings. These include the development of automatic parameterisation protocols for a variety of molecule types, the improvement of backmapping procedures, the description of protein flexibility and the development of methodologies enabling efficient sampling. We illustrate our view with examples on key areas where Martini could give important contributions such as drugs targeting membrane proteins, cryptic pockets and protein–protein interactions and the development of soft drug delivery systems.
