A set of coarse-grained two-bead-per-nucleotide models for simulations of double-stranded RNA and DNA in the CALVADOS framework are presented and it is envisioned that the CALVADOS models for double-stranded RNA and DNA will be useful for studying co-condensates of proteins and structured nucleic acids.
Abstract
Biomolecular condensates function as membraneless compartments, and some protein condensates can selectively concentrate single-stranded nucleic acids while excluding double-stranded nucleic acids. Understanding how nucleic acid structure affects partitioning into condensates has important implications for nucleic acid activity and function within condensates. Here, we present a set of coarse-grained two-bead-per-nucleotide models for simulations of double-stranded RNA and DNA in the CALVADOS framework. Our models separately represent the backbone and base, and maintain the helical structures using an elastic network potential tuned to capture chain stiffness. For dsRNA, the base stickiness was tuned using experimental data on differential partitioning of single- and double-stranded RNA into Ddx4N1 condensates in order to account for reduced base accessibility upon duplex formation. This RNA structural selectivity varied with the balance of electrostatic and non-electrostatic interactions, as revealed by simulations of condensates of the CAPRIN1 disordered region at varying ionic concentrations and with an R-to-K sequence variant. Finally, we developed parameters for double-stranded DNA using a similar approach. We envision that the CALVADOS models for double-stranded RNA and DNA will be useful for studying co-condensates of proteins and structured nucleic acids.
A generalized essential dynamics-refined ENM (edENM) is introduced for both DNA, RNA, and protein-nucleic acid complexes, parametrized against a diverse set of molecular dynamics simulations and validated using experimental ensembles from nuclear magnetic resonance, X-ray crystallography, and cryogenic electron microscopy.
Domenico Scaramozzino, Marco Cannariato, Byung Ho Lee et al.· Nucleic Acids Research· 0 citations
The sequence-dependent mechanical landscapes of double-stranded nucleic acid (dsNA) remain largely unexplored beyond canonical dsDNA. We describe cgNA+, a coarse-grained predictive model of the mechanics of dsRNA, DNA:RNA hybrids, and epigenetically modified dsDNA, all parameterised from 1.26 milliseconds of atomistic simulations. cgNA+ predicts non-local sequence-dependent equilibrium shape and stiffness with errors an order of magnitude smaller than sequence-variability, while enabling exploration of numbers of sequences inaccessible to atomistic simulation. We show that dsNA equilibrium shape is strongly influenced by flanking sequence up to octamer context, with flexible dimer-steps more context-sensitive. CpG-modification alters equilibrium shape comparable to changes caused by single-nucleotide polymorphisms. Groove width analysis across dsNA decamers reveals strong sequence dependence, reflecting the differing characteristic helical geometry of dsDNA and dsRNA, whereas DRHs exhibit mixed behaviour depending on DNA-strand pyrimidine content. CTCF binding sites exhibit a distinct groove width signature. Persistence-length spectra from ∼ 9 million sequences indicate that dsRNA is stiffer than dsDNA, whereas DRH exhibit intermediate stiffness modulated by DNA strand pyrimidine content. Persistence length increases upon CpG-modification, but decreases on hypermodification. Overall, the cgNA+ model enables a first, highly accurate, very large-scale, comparative study of sequence-dependent mechanics both within and across dsNA classes, demonstrating previously hidden regulatory layers. Graphical Abstract
Rahul Sharma, A. Patelli, R. Singh et al.· bioRxiv· 0 citations
Biomolecular condensates formed by intrinsically disordered proteins require molecular models that accurately describe proteins in both dilute solution and condensed phases. Explicit-solvent coarse-grained models offer an attractive balance between chemical resolution and computational efficiency. Yet, it remains unclear whether improving dilute-state properties is sufficient to obtain an accurate description of condensates. Here, we address this question by introducing minimal modifications to the Martini 3 force field that combine recent advances in bonded interactions with refined protein–water interactions and strengthened glycine self-interactions, while preserving the underlying chemical transferability of the model. The resulting model substantially improves the description of single-chain conformations across a diverse benchmark of disordered proteins. We then investigate phase separation of the well-characterized low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 and its sequence variants. The model reproduces several key physicochemical properties of biomolecular condensates, including chain expansion in the dense phase, sequence-dependent intermolecular contacts, protein diffusion and its relation to single-chain dimensions, and hydration, while revealing quantitative limitations in condensate density, phase equilibria, and ion partitioning. Our results show that improving dilute-state behaviour translates into a better description of condensed-phase properties, including condensate density, but is not sufficient to quantitatively reproduce the equilibrium between the dilute and dense phases.
Fran Bačić Toplek, Luís Borges-Araújo, Kresten Lindorff-Larsen et al.· bioRxiv· 0 citations
Residue-level coarse-grained simulations provide a powerful route for modeling biomolecular condensates over length and time scales that are difficult to access with atomistic molecular dynamics. Coarse-grained models have been shown to reproduce many aspects of equilibrium phase behavior. However, it remains unclear to what extent such models can reproduce the relative timescales of molecular dynamics. Here, we examine this question for complex coacervates with markedly different dynamics, formed by the highly acidic intrinsically disordered protein prothymosin α with four cationic partners: linker histone H1, protamine, polylysine, and polyarginine. Coexistence simulations using a residue-level coarse-grained model reproduce key equilibrium observables from experiments, including dense-phase concentrations, ionic-strength-dependent phase behavior, and chain dimensions in the dense and dilute phases. Dynamics are accelerated in these simulations, but a composition-specific time-rescaling factor captures the ionic-strength dependence of chain reconfiguration times within a given complex coacervate. In contrast, time rescaling is not transferable between dense and dilute phases or across condensate compositions and can depend on the chosen observable. These results show that agreement with measured equilibrium observables does not imply a universally transferable timescale for conformational dynamics in residue-level coarse-grained simulations. However, we find that the required time rescaling strongly correlates with the interaction energy of the protein chains, suggesting that the missing frictional effects arise from protein-protein interactions rather than solely from protein-solvent interactions, reminiscent of internal friction. Our findings highlight the need to combine thermodynamic validation with kinetic calibration when interpreting chain relaxation, molecular diffusion, and material properties from residue-level coarse-grained simulations of biomolecular condensates.
Soundhararajan Gopi, Han-Ling Qin, Robert B. Best et al.· bioRxiv· 0 citations
Molecular dynamics (MD) simulations are widely used to investigate membrane properties and their interactions with various plastic particles. In this tutorial, we provide guidelines for both atomistic and coarse-grained MD simulations to investigate interactions between a POPC membrane and a polystyrene (PS) nanoplastic. This tutorial is organized into a few exercises focusing on three systems: (i) PS in water, (ii) POPC membrane in water, and (iii) POPC–PS complex in water, each simulated at atomistic and coarse-grained levels. The aim of this tutorial is to familiarize readers with the process of modeling nanoplastic and membrane systems using CHARMM-GUI and performing MD simulations with GROMACS. In addition, we calculate a few biophysical properties, including the radius of gyration of PS, membrane thickness, area per lipid, order parameters, and diffusion coefficient of POPC lipids, using GROMACS analysis tools and tcl scripts. Overall, the workflow presented here provides a practical guide for readers to model, simulate, and analyze their own complex biophysical systems involving membranes and nanoplastics.
Sasthi C. Mandal, Atanu Acharya· Journal of Physical Chemistr...· 1 citation
Double‐stranded DNA molecules are sharply bent into arcs with radii on the order of 10 nanometers in the formation of nucleosomes in biology and when they are looped into minicircles for nanoscale applications. In this Personal Account, we describe our computational efforts over the past several years to understand the structure and dynamics of sharply bent DNA using molecular dynamics simulations. First, using coarse‐grained models of DNA and cationic nanoparticles, we discuss how a small difference in sequence‐dependent DNA flexibility, on the order of 10 nm in persistence length, substantially influences the structure and thermodynamics of DNA–nanoparticle complex formation. Potential of mean force calculations quantify the thermodynamic preference for nanoparticle binding to more flexible DNA, with the free energy difference arising primarily from the sequence‐dependent elastic energy of DNA bending. We then turn to all‐atom simulations of DNA minicircles with approximately 90 base pairs. Sequence‐dependent coupling between DNA bending and its helical twist is identified for specific dinucleotide steps, and the internal dynamics of poloidal rotation and in‐plane circular vibration are characterized on time scales of tens and several nanoseconds, respectively. Finally, we present our recent investigations of mechanically interlocked DNA nanostructures: rotaxanes, in which a DNA minicircle is threaded onto a linear DNA axle, and catenanes, composed of two mutually interlocked DNA minicircles. The effects of torsional stress‐induced shape distortion on the structure and dynamics of these topologically constrained architectures are discussed. Together, these studies illustrate how the interplay of DNA sequence, flexibility, and topology governs the behavior of sharply bent DNA, providing molecular‐level insights for the design of DNA‐based nanoscale devices.
Yeonho Song, Jun Soo Kim· Bulletin of the Korean Chemi...· 0 citations
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