202. MBX v1.2: Accelerating data-driven many-body molecular dynamics simulations. S. Gupta, E.F. Bull-Vulpe,

        H. Agnew, S. Iyer, X. Zhu, R. Zhou, C. Knight, F. Paesani, J. Chem. Theory Comput. 21, 1838 (2025). [link]

The MBX software provides an advanced platform for molecular dynamics simulations, leveraging state-of-the-art MB-pol

and MB-nrg data-driven many-body potential energy functions. Developed over the past decade, these potential energy

functions integrate physics-based and machine-learned many-body terms trained on electronic structure data calculated

at the ``gold standard'' coupled cluster level of theory. Recent advancements in MBX have focused on optimizing its

performance, resulting in the release of MBX v1.2. While the inherently many-body nature of MB-pol and MB-nrg ensures

high accuracy, it poses computational challenges. MBX v1.2 addresses these challenges with significant performance

improvements, including enhanced parallelism that fully harnesses the power of modern multicore CPUs. These

advancements enable simulations on nanosecond timescales for condensed-phase systems, significantly expanding the

scope of high-accuracy, predictive simulations of complex molecular systems powered by data-driven many-body potential

energy functions.

198. Dissecting the molecular structure of the air/ice interface from quantum simulations of the sum-frequency

        generation spectrum. R. Rashmi, F. Paesani, J. Am. Chem. Soc. 147, 1903 (2025). [link]

At the ice surface, water molecules form a quasi-liquid layer (QLL) with distinct properties from the bulk. Despite numerous

experimental and theoretical studies, the molecular-level understanding of this layer has remained elusive.In this work, we use

state-of-the-art quantum dynamics simulations with a realistic data-driven many- body potential to dissect the vibrational

sum-frequency generation (vSFG) spectrum in terms of contributions arising from individual molecular layers, orientations, and

hydrogen-bonding topologies that determine the QLL properties. The agreement between experimental and simulated spectra

provides a realistic view of the evolution of the QLL as a function of temperature without the need for empirical adjustments.

At lower temperatures, the emergence of specific features in the vSFG spectrum points to surface restructuring, resulting in

mixed ice Ih and ice Ic nanodomains at the surface, which may vary depending on how the air/ice interface is prepared. This

work not only underscores the critical role of many-body interactions and nuclear quantum effects in understanding ice surfaces

but also provides a definitive molecular-level picture of the QLL, which plays a central role in multiphase and heterogeneous

processes of relevance to a range of fields, including atmospheric chemistry, cryopreservation, and materials science.

204. Nuclear quantum effects and the Grotthuss mechanism dictate the pH of liquid water.

        S. Dasgupta, G. Cassone, F. Paesani, J. Phys. Chem. Lett. 16, 2996 (2025). [link]

Water’s ability to autoionize into hydronium (H3O+) and hydroxide (OH−) ions dictates the acidity or basicity of aqueous

solutions, influencing the reaction pathways of many chemical and biochemical processes. In this study, we determine the

molecular mechanism of the autoionization process by leveraging both the computational efficiency of a deep neural

network potential trained on highly accurate data calculated within density-corrected density functional theory and the

ability of enhanced sampling techniques to ensure a comprehensive exploration of the underlying multidimensional

free-energy landscape. By properly accounting for nuclear quantum effects, our simulations provide an accurate estimate

of autoionization constant of liquid water (pKw = 13.71 ± 0.16), offering a real- istic molecular-level picture of the

autoionization process and emphasizing its quantum-mechanical nature. Importantly, our simulations highlight the central

role played by the Grotthuss mechanism in stabilizing solvent-separated ion pair configurations, revealing its profound

impact on acid-base equilibria in aqueous environments.

© Paesani Research Group. All rights reserved.

200. Constraints on the location of the liquid–liquid critical point in water. F. Sciortino, Y. Zhai, S.L. Bore, F. Paesani,

        Nat. Phys. 21, 480 (2025). [link]

Over the past three decades, advancements in computational modeling – particularly through the advent of data-driven

many-body potentials rigorously derived from “first principles” and augmented by the efficiency of neural networks – have

significantly enhanced the accuracy of molecular simulations, enabling the exploration of the phase behavior of water with

unprecedented realism. Our study leverages these computational advances to probe the elusive liquid-liquid transition in

supercooled water. For the first time, microsecond-long simulations with chemical accuracy, conducted over several years,

provide compelling evidence that water indeed exists in two discernibly distinct liquid states at low temperature and high

pressure. By pinpointing a realistic estimate for the location of the liquid-liquid critical point at ~200 K and ~1050 atm, our

study not only advances current understanding of water’s anomalous behavior but also establishes a basis for experimental

validation. Importantly, our simulations indicate that the liquid-liquid critical point falls within tem- perature and pressure

ranges that could potentially be experimentally probed in water nanodroplets, opening the possibility for direct measurements.

203. Structure-activity relationships in ether-functionalized solid-state metal-organic framework electrolytes.

        A.U. Mu, V.V. Singh, H. Kim, D.J. Lee, N. Kim, C.X. Ruff, A. Levy, T.A. Young, F. Paesani, S.M. Cohen, T.A. Pascal,

        Z. Chen, Chem. Mater. 37, 2783 (2025). [link]

In this study, we carried out a systematic investigation of twelve Zr(IV)-based UiO-66 MOFs with varying ether-chain functional

groups out to elucidate the critical microscopic interactions that facilitate improved solid-state electrolyte performance.

We employed enhanced sampling MD simulations that revealed a three-tier ion hopping mechanism: linker-linker hopping,

linker-counterion hopping, and counterion-counterion hopping. As a result, we were able to tune the ion conductivities by

means of rationally manipulating the counterion distributions, linker binding strengths, and the configurational entropy. The

resulting performance of these MOF-based solid-state electrolytes was significantly enhanced, with a methoxy-functionalized

framework (UiO-66-L1-100) achieving high ionic conductivities of 2.32×10-4 S/cm and 2.07×10-3 S/cm at 30 °C and 90 °C,

respectively, a magnitude greater than other all-solid-state MOF electrolyte systems. The electrolyte stability was evaluated

with LiIn|LPSCl|MOF:LiTFSI|LPSCl|LiIn symmetric cells, showing excellent Li plating/stripping processes.

199. Electroreduction-driven formation and connectivity of polyoxometalate coordination networks.

        H. Chang, L. Chen, E. Samolova, Y. Pan, K.A. Acosta, C.E.Lemmon, M. Gembicky, F. Paesani, A.M. Schimpf,

        Inorg. Chem. 64, 1630 (2025). [link]

We present the synthesis of metal oxide coordination networks based on Preyssler-type polyoxoanions ([NaP5W30O110]14− and

[NaP5MoW29O110]14−) bridged with metal–aquo complexes ([M(H2O)n]m+, Mm+ = Co2+, Ni2+, Zn2+, Y3+), induced by

electrochemical reduction. Networks bridged with first-row transition metals are isostructural with a previously reported Co-bridged

structure, while the Y3+–bridged structure is new. All networks feature an uncommon binding motif of the metal cation to the

oxygen atoms at cap positions, which we hypothesize is due to increased electron density at the cap upon reduction. Oxidation of

a Zn2+–bridged network results in a new structure in which Zn2+–Ocap bonds are lost, indicating the importance of reduction in

the connectivity of these polyoxometalate coordination networks.

201. Revealing water structure at neutral and charged graphene/water interfaces through quantum simulations of

        sum-frequency generation spectra. R. Rashmi, T.O. Balogun, G. Azom, H. Agnew, R. Kumar, F. Paesani,

        ACS Nano. 19, 4876 (2025). [link]

Leveraging the realism of the MB-pol data-driven many-body potential and advanced path-integral quantum dynamics, we

analyze the vibrational sum-frequency generation (vSFG) spectrum of graphene/water interfaces under varying surface

charges. Our quantum simulations reveal a distinctive dangling OH peak in the vSFG spectrum at neutral graphene,

consistent with recent experimental findings yet markedly different from earlier studies. As the graphene surface becomes

positively charged, interfacial water molecules reorient, decreasing the intensity of the dangling OH peak as the OH groups

turn away from the graphene. In contrast, water molecules orient their OH bonds toward negatively charged graphene, leading

to a prominent dangling OH peak in the corresponding vSFG spectrum. This charge-induced reorganization generates a

diverse range of hydrogen-bonding topologies at the interface, which extend into deeper water layers, creating an unequal

distribution of molecules with OH bonds pointing toward and away from the graphene sheet.

206. Permutationally invariant Fourier series for accurate and robust data-driven many-body potentials.

        X. Zhu, F. Paesani, under review. [link]

We present a robust solution to the long-standing challenge of eliminating unphysical energy predictions, or ``holes,''

in machine-learned many-body potentials, which can destabilize simulations when encountering configurations

beyond the training set. By leveraging permutationally invariant Fourier series (PIFSs) within the MB-nrg data-driven

many-body formalism, we introduce a new approach that significantly enhances the numerical stability of MB-nrg

potential energy functions (PEFs) while preserving accuracy and transferability. Unlike conventional strategies that

attempt to ``plug holes'' by expanding training datasets, PIFSs provide a more fundamental and efficient means of

ensuring physically meaningful extrapolation across diverse molecular configurations. Using water as a benchmark

system, we demonstrate that the MB-pol(PIFS) PEF retains the high accuracy of MB-pol across gas and condensed

phases while extending the PEF’s stability to a much broader range of thermodynamic conditions. Our results

suggest that the PIFS-based MB-nrg many-body formalism provides a general framework for constructing accurate

and robust physics-based/machine-learned potentials applicable to a broad range of molecular systems.

209. Density-functionalized QM/MM delivers chemical accuracy for solvated systems. X. Chen, J. Martinez, X. Shao,

         M. Riera, F. Paesani, O. Andreussi, M. Pavanello, under review. [link]

We present a reformulation of QM/MM as a fully quantum mechanical theory of interacting subsystems, all treated at

the level of density functional theory (DFT). For the MM subsystem, which lacks orbitals, we assign an ad hoc electron

density and apply orbital-free DFT functionals to describe its quantum properties. The interaction between the QM and

MM subsystems is also treated using orbital-free density functionals, accounting for Coulomb interactions, exchange,

correlation, and Pauli repulsion. Consistency across QM and MM subsystems is ensured by employing data-driven,

many-body MM force fields that faithfully represent DFT functionals. Applications to water-solvated systems demonstrate

that this approach achieves unprecedented, very rapid convergence to chemical accuracy as the size of the QM

subsystem increases. We validate the method with several pilot studies, including water bulk, water clusters

(prism hexamer and pentamers), solvated glucose, a palladium aqua ion, and a wet monolayer of MoS2.

205. Thermodynamics of alkali metal ion uptake from aqueous solution in MOF-808. Y. Pan, S. Saha, M. Burigana,

        V. Singh, O.M. Yaghi, F. Paesani, under review. [link]

In this study, we employ free-energy calculations and enhanced sampling simulations to investigate alkali metal ion

uptake in MOF-808, a prototypical hydrothermally stable MOF. Our results reveal that large pores provide a similarly

stable environment for all studied ions, indicating a lack of intrinsic selectivity, whereas small pores exhibit distinct

thermodynamic and kinetic preferences that govern ion uptake. Dehydrated alkali metal ions are stable within small

pores, and free-energy profiles reveal that their transfer from large to small pores occurs with lower energy barriers

than that of water molecules. Among these ions, Li+ faces the highest barrier due to its strong hydration shell,

whereas K+ exhibits the greatest thermodynamic preference for uptake in its dehydrated state. However, within

hydrated small pores, Li+ is the most stable, underscoring the interplay between hydration structure and confinement

effects. These findings provide fundamental insights into ion uptake in MOFs and offer guidance for designing

next-generation MOFs with enhanced selectivity for metal ion extraction from dilute solutions. Future efforts should

explore pore functionalization to optimize MOFs for efficient and selective metal recovery.

207. Computational analysis of threonine ladders on distinct beta-solenoid scaffolds, with implications for the

        design of novel antifreeze proteins. C.N. Calia, F. Paesani, under review. [link]

Beta-solenoids exist in nature in numerous forms and emerging protein design technologies may afford opportunities

to diversify them furher, suggesting the possibility of creating a variety of new AFPs by installing a threonine ladder

on non-AFP natural or designed beta-solenoids. In this study, we determine if and how specific solenoid scaffolds

significantly affect a threonine ladder’s structural characteristics (and thus its suitability for ice binding). To this end,

we created distinct variants of a model beta-solenoid for in silico analysis via structure prediction and molecular

dynamics simulations. Our findings indicate that the concavity of the beta-solenoid face on which a threonine ladder

is arrayed can substantially influence the local geometry of the threonines, with less concave examples resembling

the AFP TmAFP and a more concave example losing the ordered channel waters present in well-studied natural

ice-binding surfaces. Disparities in concavity and threonine hydroxyl spacings appeared initially in our AlphaFold

results and were supported by the simulations, illustrating AlphaFold’s possible utility for high-throughput preliminary

screening of designed beta-solenoid AFP sequence candidates.

208. Data-driven many-body simulations of biomolecules with CCSD(T) accuracy: I. Polyalanine in the Gas Phase.

        R. Zhou, E.F. Bull-Vulpe, Y. Pan, F. Paesani, under review. [link]

A predictive understanding of how proteins fold, misfold, and stabilize requires accurate molecular-level insights into

the thermodynamic and kinetic forces shaping their backbones. While empirical force fields remain the workhorse of

biomolecular simulations, their limited functional forms often fall short in capturing the complex many-body

interactions that govern protein dynamics. Quantum-mechanical methods, on the other hand, offer high accuracy but

are prohibitively expensive for large biomolecules. In this work, we introduce a generalized, intramolecular formulation

of the data-driven many-body MB-nrg formalism that achieves "gold standard" coupled cluster accuracy in simulating

polyalanine chains in the gas phase. By decomposing polyalanines into chemically intuitive building blocks, we

develop modular and transferable potential energy functions that accurately reproduce reference energies,

normal-mode harmonic frequencies, and conformational free-energy landscapes. This work paves the way for

"gold standard" coupled cluster-level simulations of proteins under physiologically relevant conditions, bridging

the gap between chemical accuracy and biological complexity.

210. Molecular insights into the influence of ions on water structure. II. Halide ions in solution. H. Agnew, R. Savoj,

        R. Rashmi, B. Savala, F. Paesani, under review. [link]

Understanding how halide ions affect the structure and dynamics of water at the molecular level is essential for a wide

range of chemical, biological, and environmental processes. In this study, we use molecular dynamics simulations with

MB-nrg data-driven many-body potential energy functions to investigate the hydration properties of halide ions in bulk

water. The results reveal distinct trends in hydration structure, residence times, dipole moment distributions, and

infrared spectral signatures, reflecting variations in ion size, charge density, and polarizability. In particular, fluoride

promotes uniquely strong and more directional hydrogen bonds with the surrounding water molecules, which leads to

substantial spectral shifts and slower water exchange dynamics. In contrast, heavier halides induce only minimal

perturbations on the water hydrogen-bond network, even within the first hydration shell. These insights provide a

quantitative framework for understanding ion-specific effects in aqueous systems and set the stage for future studies

of more complex environments such as aqueous interfaces and confined systems.

211. Resolving the spectral signatures of strong hydrogen bonding in fluoride hydration. R. Rashmi, B. Savala,

        H. Agnew, R. Savoj, F. Paesani, under review. [link]

The fluoride ion forms some of the strongest hydrogen bonds in aqueous solution, making its hydration shell

an ideal system to probe the interplay between ion–water interactions, hydrogen-bond dynamics, and nuclear

quantum effects (NQEs). In this study, we integrate MB-nrg data-driven many-body potential energy functions

with advanced quantum dynamics simulations to uncover how many-body interactions and NQEs shape the

structure and vibrational response of hydrated fluoride. Our analysis reveals that short-range three-body

interactions between the ion and surrounding water molecules are critical for capturing the infrared spectral

features of the first hydration shell, particularly in the OH-stretch and libration regions. We identify distinct

reorientation dynamics of OH bonds that give rise to the bifurcation of the libration band. While NQEs induce a

redshift in OH-stretching frequencies, they have minimal influence on orientational and translational dynamics.

These results underscore the importance of rigorous many-body treatments to achieve predictive accuracy in

modeling ion hydration and interpreting vibrational spectra.