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Experimental data-guided parameterization and validation of an AMBER protein force field

An improved force field is developed, derived from its parent, Amber ff24EXP-GA, and its evaluation against Amber ff14SB and other contemporary force fields, such as CHARMM36m, in capturing the empirically determined conformational properties of unfolded systems: short peptides that serve as model systems for IDPs, and longer unfolded proteins.

Athul Suresh, B. Urbanc · 0 citations
Preprint Jul 2026

Structure, Diffusion, and Relaxation in a Charge-Neutral ProTalpha-Histone H1 Condensate

Condensates formed by oppositely charged intrinsically disordered proteins provide model systems for understanding how transient electrostatic interactions govern structure and dynamics in biomolecular assemblies. Here we investigate a nearly charge-neutral condensate composed of 50 Prothymosin alpha (ProTalpha) and 40 Histone H1 molecules using a single-bead-per-residue coarse-grained model combining the HPS hydropathy model for disordered regions with a Go model for the globular domain of Histone H1 under NPT conditions at pressures from 2 to 12 bar. We find that chain dimensions, including the radius of gyration (Rg), end-to-end distance (Ree), and their ratio R, are insensitive to pressure, indicating that chain conformations remain largely unchanged over the pressure range studied. Histone H1 exhibits systematically larger values of R than ProTalpha because of its globular-core plus disordered-tail architecture. Translational diffusion coefficients decrease monotonically with pressure, from approximately 0.22 to 0.06 nm^2/ns, with substantial chain-to-chain heterogeneity comparable to the mean diffusion coefficient. Chain relaxation follows a stretched exponential with beta less than 1 that decreases with pressure. ProTalpha relaxation times of approximately 12 to 40 ns obey Rouse scaling, whereas Histone H1 deviates because of the internal constraint imposed by its globular domain. ProTalpha-Histone H1 contact lifetimes of approximately 0.43 to 0.56 ns are much shorter than the Rouse relaxation time, placing the system firmly in the fast-exchange regime where transient electrostatic contacts renormalize chain friction rather than acting as permanent cross-links, consistent with the moderate stretching exponent beta of approximately 0.55 to 0.70 observed across all pressures.

A. Bhattacharya · 0 citations
Open access Jul 2026

Development of United-Atom Force Fields for Monomeric and Oligomeric Ionic Liquids through Regression-Guided Optimization of Electronic Continuum Correction Parameters

Ionic liquids are salts that exist in the liquid state at room temperature and exhibit high viscosity because of their strong electrostatic interactions. It was difficult to reproduce their viscosity by molecular dynamics simulations with conventional nonpolarizable force fields; however, recent development of force fields implementing electronic continuum correction (ECC), which accounts for polarizability, has enabled accurate predictions. Here, we present a regression-guided strategy to optimize scaling factors for ECC charges and Lennard-Jones parameters for monomeric (BMIM+, MOEMIM+) and oligomeric (IL22+, IL44+) imidazolium-based cations paired with TFSI– with united-atom models. The scaling factors were optimized to simultaneously reproduce experimental density and viscosity. To validate the strategy, we calculated the temperature dependence of density, diffusion coefficient, conductivity, and viscosity of BMIM–TFSI, achieving good agreements with experiments. Moreover, scaling factors optimized for MOEMIM+, which shares similar chemical structure and elemental compositions with IL22+ and IL44+, were found to be transferable to these compounds. Thus, this work not only provides a practical regression-guided workflow for selecting ECC-based united-atom force-field parameters but also suggests their transferability across chemically related ionic liquids.

Md Fahim Newaz, Takahiko Ikarashi, Takeshi Fukuma et al. · 0 citations
#protein folding Open access Aug 2026

Biomolecular Condensates Dictate the Folding Landscape of Protein Alpha-Helices

This work investigates how protein folding landscapes are altered inside condensates, using the protein α-helix as a model folded domain and develops a chemically specific, residue-resolution model for quantification of α-helical folding and applies it to characterize diverse helices within condensates of varying physicochemical properties.

Nathaniel Hess, Jerelle A. Joseph · 0 citations
Open access Jul 2026

Solvent-buffer effects in molecular dynamics simulations of nucleic acids

Molecular dynamics simulations of nucleic acids are performed using a solvent-buffer distance of 10 Å between the solute surface and the simulation box boundary. Although this cell size has been extensively explored in protein simulations, its implications for nucleic acid dynamics are not well understood. Nucleic acids are elongated, highly charged, and flexible structures with hydration and dynamical properties distinct from those of proteins and therefore, they may require different solvent-layer considerations in simulations. In this study, we investigated the effect of simulation cell size on nucleic acid dynamics by simulating a 30-base-pair double-helical nucleic acid structure and its two single-stranded forms using solvent-buffer distances of 3, 5, 10, 15, and 20 Å. Smaller cells may impose restricted hydration, molecular crowding, and periodic image interactions. However, larger cells provide solvent space for conformational relaxation. A total of 45 µs of molecular dynamics simulations were performed (3 structures × 5 cell sizes × 3 replicates × 1 µs). Our results show that while the commonly used 10 Å buffer may be sufficient to maintain the stability of the double-stranded nucleic acid, larger cells are required to capture the conformational dynamics of single-stranded structures. In both, increasing the cell size to 15 or 20 Å enables broader conformational sampling. The first hydration shell exhibits reduced crowding in the 20 Å cell, consistent with more relaxed conformations. At larger cell sizes, single-stranded nucleic acids adopt compact, self-associated conformations for stability. Together, this study presents physical insight into how simulation cell size and solvent environment influence nucleic acid dynamics.

Nainsy Baghel, Pranchal Shrivastava, R. Mehra · 0 citations
Preprint Jul 2026

Aromatic Molecule Solvation in Liquid Water with Coupled Cluster Accuracy: The Balance of Pi-Interactions and Hydrophobicity

Aromatic organic solutes in water exhibit a delicate balance between hydrophobic solvation and directional O-H$\cdots \pi$ hydrogen bonds, yet widely used force fields and state-of-the-art density functional approaches struggle to provide a consistent picture of these pivotal interactions. We introduce a data-efficient upfitting strategy to train a machine learning interatomic potential (MLIP) based on the graph atomic cluster expansion for aqueous aromatic molecules with CCSD(T) accuracy for condensed phase simulations, using only finite molecular clusters. We apply our method to aqueous toluene (C$_6$H$_5$CH$_3$). The resulting CCSD(T)-quality MLIP reproduces coupled cluster energies and forces in bulk and reveals that commonly employed methods do not capture the crucial balance between hydrophilic and hydrophobic solvation, distorting the interactions of aromatic molecules with their environment. Representative biomolecular force fields substantially understructure the hydrophobic solvation shell and misorient interfacial water, while overestimating $\pi$-contacts, yielding an inconsistent solvation balance. Even hybrid DFT and MP2 overestimate barriers to breaking of water-$\pi$ hydrogen bonds. Our workflow provides a practical, general route to CCSD(T)-quality condensed-phase simulations of aqueous solutions, and thus constructed interaction potentials now open the door to consistent, highly accurate benchmark studies of $\pi$-contacts and hydrophobic effects in biomolecular contexts such as solvation of proteins and DNA in aqueous environments.

N. Stolte, H. Forbert, Yu. Lysogorskiy et al. · 0 citations

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