Anisotropic Electrostatic Interactions in Coarse-Grained Water Models to Enhance the Accuracy and Speed-Up Factor of Mesoscopic Simulations
Ontology highlight
ABSTRACT:
SUBMITTER: Bellussi F
PROVIDER: S-EPMC8573754 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Electrostatic interactions play a pivotal role in many biomolecular processes. The molecular organization and function in biological systems are largely determined by these interactions. Owing to the highly negative charge of RNA, the effect is expected to be more pronounced in this system. Moreover, RNA base pairing is dependent on the charge of the base, giving rise to alternative secondary and tertiary structures. The equilibrium between uncharged and charged bases is regulated by the solution pH, which is therefore a key environmental condition influencing the molecule's structure and behaviour. By means of constant-pH Monte Carlo simulations based on a fast proton titration scheme, coupled with the coarse-grained model HiRE-RNA, molecular dynamic simulations of RNA molecules at constant pH enable us to explore the RNA conformational plasticity at different pH values as well as to compute electrostatic properties as local pK a values for each nucleotide.
| S-EPMC6501344 | biostudies-literature
Project description:Using the endosomal sorting complex required for transport (ESCRT)-III membrane remodeling complex as an example, we analyze three popular coarse-grained models (the regular MARTINI, polarizable MARTINI (POL-MARTINI), and big multipole water MARTINI (BMW-MARTINI)) for the description of membrane curvature sensing and generation activities of peripheral proteins. Although the three variants of the MARTINI model provide consistent descriptions for the protein-protein interface in a linear filament model of ESCRT-III, they differ considerably in terms of protein-membrane interface and therefore membrane curvature sensing and generation behaviors. In particular, BMW-MARTINI provides the most consistent description of the protein-membrane interface as compared to all-atom simulations, whereas the regular MARTINI is most consistent with atomistic simulations in terms of the qualitative sign of membrane curvature sensing and generation. With POL-MARTINI, the ESCRT-III model interacts weakly with the membrane and therefore does not exhibit any curvature-sensitive activities. Analysis suggests that the incorrect membrane curvature activities predicted by BMW-MARTINI are due to overestimated insertion depth of an amphipathic helix and incorrect sign for the spontaneous curvature of anionic lipids. These results not only point to ways that coarse-grained models can be improved but also explicitly highlight local lipid composition and insertion depth of protein motifs as essential regulatory factors for membrane curvature sensing and generation.
| S-EPMC8390925 | biostudies-literature
Project description:We develop a sequence based alpha-carbon model to incorporate a mean field estimate of the orientation dependence of the polypeptide chain that gives rise to specific hydrogen bond pairing to stabilize alpha-helices and beta-sheets. We illustrate the success of the new protein model in capturing thermodynamic measures and folding mechanism of proteins L and G. Compared to our previous coarse-grained model, the new model shows greater folding cooperativity and improvements in designability of protein sequences, as well as predicting correct trends for kinetic rates and mechanism for proteins L and G. We believe the model is broadly applicable to other protein folding and protein-protein co-assembly processes, and does not require experimental input beyond the topology description of the native state. Even without tertiary topology information, it can also serve as a mid-resolution protein model for more exhaustive conformational search strategies that can bridge back down to atomic descriptions of the polypeptide chain.
| S-EPMC3474853 | biostudies-literature
Project description:The interaction of ?-helical peptides with lipid bilayers is central to our understanding of the physicochemical principles of biological membrane organization and stability. Mutations that alter the position or orientation of an ?-helix within a membrane, or that change the probability that the ?-helix will insert into the membrane, can alter a range of membrane protein functions. We describe a comparative coarse-grained molecular dynamics simulation methodology, based on self-assembly of a lipid bilayer in the presence of an ?-helical peptide, which allows us to model membrane transmembrane helix insertion. We validate this methodology against available experimental data for synthetic model peptides (WALP23 and LS3). Simulation-based estimates of apparent free energies of insertion into a bilayer of cystic fibrosis transmembrane regulator-derived helices correlate well with published data for translocon-mediated insertion. Comparison of values of the apparent free energy of insertion from self-assembly simulations with those from coarse-grained molecular dynamics potentials of mean force for model peptides, and with translocon-mediated insertion of cystic fibrosis transmembrane regulator-derived peptides suggests a nonequilibrium model of helix insertion into bilayers.
| S-EPMC3077683 | biostudies-literature
Project description:Holliday junctions play a central role in genetic recombination, DNA repair and other cellular processes. We combine simulations and experiments to evaluate the ability of the 3SPN.2 model, a coarse-grained representation designed to mimic B-DNA, to predict the properties of DNA Holliday junctions. The model reproduces many experimentally determined aspects of junction structure and stability, including the temperature dependence of melting on salt concentration, the bias between open and stacked conformations, the relative populations of conformers at high salt concentration, and the inter-duplex angle (IDA) between arms. We also obtain a close correspondence between the junction structure evaluated by all-atom and coarse-grained simulations. We predict that, for salt concentrations at physiological and higher levels, the populations of the stacked conformers are independent of salt concentration, and directly observe proposed tetrahedral intermediate sub-states implicated in conformational transitions. Our findings demonstrate that the 3SPN.2 model captures junction properties that are inaccessible to all-atom studies, opening the possibility to simulate complex aspects of junction behavior.
| S-EPMC4789735 | biostudies-other
Project description:Many biological cellular processes occur at the micro- or millisecond time scale. With traditional all-atom molecular modeling techniques it is difficult to investigate the dynamics of long time scales or large systems, such as protein aggregation or activation. Coarse graining (CG) can be used to reduce the number of degrees of freedom in such a system, and reduce the computational complexity. In this paper the first version of a coarse grained model for transmembrane proteins is presented. This model differs from other coarse grained protein models due to the introduction of a novel angle potential as well as a hydrogen bonding potential. These new potentials are used to stabilize the backbone. The model has been validated by investigating the adaptation of the hydrophobic mismatch induced by the insertion of WALP-peptides into a lipid membrane, showing that the first step in the adaptation is an increase in the membrane thickness, followed by a tilting of the peptide.
| S-EPMC2904924 | biostudies-literature
Project description:Deoxyribozymes (DNAzymes) are single-stranded DNA that catalyze nucleic acid biochemistry. Although a number of DNAzymes have been discovered by in vitro selection, the relationship between their tertiary structure and function remains unknown. We focus here on the well-studied 10-23 DNAzyme, which cleaves mRNA with a catalytic efficiency approaching that of RNase A. Using coarse-grained Brownian dynamics simulations, we find that the DNAzyme bends its substrate away from the cleavage point, exposing the reactive site and buckling the DNAzyme catalytic core. This hypothesized transition state provides microscopic insights into experimental observations concerning the size of the DNAzyme/substrate complex, the impact of the recognition arm length, and the sensitivity of the enzymatic activity to point mutations of the catalytic core. Upon cleaving the pertinent backbone bond in the substrate, we find that the catalytic core of the DNAzyme unwinds and the overall complex rapidly extends, in agreement with experiments on the related 8-17 DNAzyme. The results presented here provide a starting point for interpreting experimental data on DNAzyme kinetics, as well as developing more detailed simulation models. The results also demonstrate the limitations of using a simple physical model to understand the role of point mutations.
| S-EPMC2776252 | biostudies-literature
Project description:Despite the high fidelity of bottom-up coarse-grained (CG) approaches to recapitulate the structural correlations in atomistic simulations, the general use of bottom-up CG methods is limited because of the nontransferable nature of these CG models under different thermodynamic conditions. Because bottom-up CG potentials usually correspond to configuration-dependent free energies of the system, recent studies have focused on adjusting enthalpic or entropic contributions to account for issues with transferability. However, these approaches can require a manual adjustment of the CG interaction a priori and are usually limited to constant volume ensembles. To overcome these limitations, we construct temperature and phase transferable CG models under constant pressure by developing the ultra-coarse-graining (UCG) methodology in the mean-field limit. In the mean-field ansatz, an embedded semi-global order parameter recapitulates global changes to the system by automatically adjusting the effective CG interactions, thus bridging free energy decompositions with UCG theory. The method presented is designed to faithfully capture structural correlations under different thermodynamic conditions, using a single UCG model. Specifically, we test the applicability of the developed theory in three distinct cases: (1) different temperatures at constant pressure in liquids, (2) different temperatures across thermodynamic phases, and (3) liquid/vapor interfaces. We demonstrate that the systematic construction of both temperature and phase transferable bottom-up CG models is possible using this generalized UCG theory. Based on our findings, this approach significantly extends the transferability and applicability of the bottom-up CG theory and method.
| S-EPMC8631167 | biostudies-literature
Project description:Maculatin 1.1 (M1.1) is a membrane-active antimicrobial peptide (AMP) from an Australian tree frog that forms a kinked amphipathic alpha-helix in the presence of a lipid bilayer or bilayer-mimetic environment. To help elucidate its mechanism of membrane-lytic activity, we performed a total of approximately 8 micros of coarse-grained molecular dynamics (CG-MD) simulations of M1.1 in the presence of zwitterionic phospholipid membranes. Several systems were simulated in which the peptide/lipid ratio was varied. At a low peptide/lipid ratio, M1.1 adopted a kinked, membrane-interfacial location, consistent with experiment. At higher peptide/lipid ratios, we observed spontaneous, cooperative membrane insertion of M1.1 peptide aggregates. The minimum size for formation of a transmembrane (TM) aggregate was just four peptides. The absence of a simple and well-defined central channel, along with the exclusion of lipid headgroups from the aggregates, suggests that a pore-like model is an unlikely explanation for the mechanism of membrane lysis by M1.1. We also performed an extended 1.25 micros simulation of the permeabilization of a complete liposome by multiple peptides. Consistent with the simpler bilayer simulations, formation of monomeric interfacial peptides and TM peptide clusters was observed. In contrast, major structural changes were observed in the vesicle membrane, implicating induced membrane curvature in the mechanism of active antimicrobial peptide lysis. This contrasted with the behavior of the nonpore-forming model peptide WALP23, which inserted into the vesicle to form extended clusters of TM alpha-helices with relatively little perturbation of bilayer properties.
| S-EPMC2553143 | biostudies-literature
Project description:A simple coarse-grained model of mucus structure and dynamics is proposed and evaluated. The model is based on simple cubic, face-centered lattice representation. Mucins are simulated as lattice chains in which each bead of the model chains represents a mucin domain, equivalent to its Kuhn segment. The remaining lattice sites are considered to be occupied by the solvent. Model mucins consist of three types of domains: polar (glycosylated central segments), hydrophobic, and cysteine-rich, located at the terminal part of the mucin chains. The sequence of these domains mimics the sequence of real mucins. Static and dynamic properties of the system were studied by means of Monte Carlo dynamics. It was shown that the model system undergoes sol-gel transition and that the interactions between hydrophobic domains are responsible for the transition and characteristic properties of the dynamic network in the gel phase. Cysteine-rich domains are essential for frictional properties of the system. Structural and dynamic properties of the model mucus observed in simulations are in qualitative agreement with known experimental facts and provide mechanistic explanation of complex properties of real mucus.
| S-EPMC2998598 | biostudies-literature