142. Infrared signatures of isomer selectivity and symmetry breaking in the Cs+(H2O)3 complex using many-body

        potential energy functions. M. Riera, J.J. Talbot, R.P. Steele, F. Paesani. J. Chem. Phys. 153, 044306 (2020). [link]

A quantitative description of the interactions between ions and water is key to characterizing the role played

by ions in mediating fundamental processes that take place in aqueous environments. At the molecular level,

vibrational spectroscopy provides a unique means to probe the multidimensional potential energy surface of

small ion−water clusters. In this study, we combine the MB-nrg potential energy functions recently developed

for ion−water interactions with perturbative corrections to vibrational self-consistent field theory and the

local-monomer approximation to disentangle many-body effects on the stability and vibrational structure

of the Cs+(H2O)3 cluster. Since several low-energy, thermodynamically accessible isomers exist for

Cs+(H2O)3, even small changes in the description of the underlying potential energy surface can result in

large differences in the relative stability of the various isomers. Our analysis demonstrates that a quantitative

account for three-body energies and explicit treatment of cross-monomer vibrational couplings are required

to reproduce the experimental spectrum.

© Paesani Research Group. All rights reserved.

137. Modeling spontaneous charge transfer at metal/organic hybrid heterostructures. V.O. Özçelik, Y. Li, W. Xiong,

        F. Paesani. J. Phys. Chem. C 124, 4802 (2020). [link]

Using various metal/poly(3- hexylthiophene)(P3HT) heterostructure models, we reveal that the level of

spontaneous charge transfer and electronic coupling at these interfaces depend on the conformational

regularity of the organic polymer deposited on the metal substrate. Using ab-initio quantum chemical

calculations based on density functional theory (DFT) and heterodyne vibrational sum frequency

generation (HD-VSFG) measurements, we show that inducing regio-randomness into the organic polymer

mod- ifies the intensity of interfacial electronic states, level of hybridization, density of interfacial charge

transfer and the electronic wave function of the material. We present the HD-VSFG responses of the

metal/P3HT heterojunctions containing both regio-regular and regio-random P3HT structures and show

that the amount of non-resonant signal is closely related to the level of the spontaneous charge transfer

at the interface. Thus, by measuring the non-resonant response of the metal/P3HT heterojunctions,

the level of spontaneous charge transfer at the interface can be determined.

138. Computer simulations explain mutation-induced structural and functional effects on the DNA editing

        efficiency of adenosine base editors. K.L. Rallapalli, A.C. Komor, F. Paesani. Sci. Adv.  6, eaaz2309 (2020). [link]

Adenine base editors (ABEs), facilitate the efficient modification of A:T base pairs to G⋮C at targeted genomic

loci via the deamination of adenine to inosine. ABEs were developed by engineering and evolving a tRNA

adenosine deaminase enzyme (TadA) into a single-stranded DNA (ssDNA) editing enzyme. A mechanistic

understanding of the contributions of the individual mutations to ssDNA editing efficiency of ABEs remains

unknown. Here, we use MD simulations to explore the structural and functional role played by the initial

mutations in the onset of ssDNA modifying activity of the TadA enzyme. Atomistic insights into the system

reveal that these early mutations lead to intricate conformational changes in the structure of the protein.

In particular, the first mutation, Asp108Asn, is associated with an enhancement in the binding free energy

of the TadA* to ssDNA. Simulations and experimental reversion analyses verify the importance of this single

mutation in imparting functional promiscuity to the TadA enzyme and suggest that the enzyme performs

base editing as a monomer rather than a dimer.

139. Data-driven many-body models for molecular fluids: CO2/H2O mixtures as a case study. M. Riera, E.P. Yeh,

        F. Paesani. J. Chem. Theory Comput. 16, 2246 (2020). [link]

In this study, we extend the scope of the many-body TTM-nrg and MB-nrg potential energy functions (PEFs),

originally introduced for halide ion–water and alkali-metal ion–water interactions, to the modeling of carbon

dioxide and water mixtures as prototypical examples of molecular fluids. Both TTM-nrg and MB-nrg PEFs

are derived entirely from electronic structure data obtained at the coupled cluster level of theory and are,

by construction, compatible with MB-pol, a many-body PEF that has been shown to accurately reproduce

the properties of water. By providing a physically correct description of many-body effects at both short and

long ranges, the MB-nrg PEFs are shown to quantitatively represent the global potential energy surfaces

of the CO2–CO2 and CO2–H2O dimers and the energetics of small clusters as well as to correctly reproduce

various properties in both gas and liquid phases. Building upon previous studies of aqueous systems, our

analysis provides further evidence for the accuracy and efficiency of the MB-nrg framework in representing

molecular interactions in fluid mixtures at different thermodynamic conditions.

140. Active learning of many-body configuration space: Application to the Cs+–water MB-nrg potential energy

        function as a case study. Y. Zhai, A. Caruso, S. Gao, F. Paesani. J. Chem. Phys. 152, 144103 (2020). [link]

The efficient selection of representative configurations that are used in high-level electronic structure

calculations needed for the development of many-body molecular models poses a challenge to current

data-driven approaches to molecular simulations. Here, we introduce an active learning (AL) framework

for generating training sets corresponding to individual many-body contributions to the energy of a

N-body system, which are required for the development of MB-nrg potential energy functions (PEFs).

Our AL framework is based on uncertainty and error estimation, and uses Gaussian process regression

to identify the most relevant configurations that are needed for an accurate representation of the energy

landscape of the molecular system under exam. Considering the computational cost associated with

high-level electronic structure calculations for training set configurations, our AL framework is particularly

well-suited to the development of many-body PEFs, with chemical and spectroscopic accuracy, for

molecular simulations from the gas to condensed phase.

141. On the nature of alkali ion−water interactions: Insights from many-body representations and density

        functional theory. II. C.K. Egan, B.B. Bizzarro, M. Riera, F. Paesani. J. Chem. Theory Comput. 16, 3055 (2020). [link]

Interaction energies of alkali ion−water dimers, M+(H2O), and trimers, M+(H2O)2, with M = Li, Na, K, Rb,

Cs, are investigated using various many-body potential en- ergy functions, and exchange correlation

functionals selected across the hierarchy of density functional theory approximations. Analysis of

interaction energy decomposi- tions indicates that close range interactions such as Pauli repulsion,

charge transfer, and charge penetration must be captured in order to reproduce accurate interaction

energies. In particular, it is found that simple classical polarizable models must be supplemented with

dedicated terms which account for these close range interactions in order to achieve chemical

accuracy across configuration space. It is also found that the XC functionals mostly differ from each

other in their Pauli repulsion + dispersion energies, and hence benefit from the inclusion of nonlocal

terms such as Hartree-Fock exchange and dependence on the electronic kinetic energy density in

order to reproduce the interactions that contribute to this term, namely Pauli repulsion and dispersion.

143. How good are polarizable and flexible models for water: Insights from a many-body perspective.

        E. Lambros, F. Paesani. J. Chem. Phys. 153, 060901 (2020). [link]

We present a systematic analysis of state-of-the-art polarizable water models from a many-body

perspective, with a specific focus on their ability to represent the Born-Oppenheimer potential energy

surface of water from the gas to the liquid phase. Using coupled cluster data in the completed basis

set limit as a reference, we examine the accuracy of the polarizable models in reproducing many-body

contributions to interaction energies and harmonic frequencies of water clusters and compare their

performance with that of MB-pol, an explicit many-body model that has been shown to correctly

predict the properties of water across the entire phase diagram. We find that, while they are able to

reproduce the energetics of minimum-energy structures, the polarizable models examined here suffer

from inadequate representations of many-body effects for distorted configurations. We believe that

future developments of both polarizable and explicit many-body models should continue in parallel

and would benefit from synergistic efforts aimed at integrating the best aspects of the two frameworks.

144. A many-body, fully polarizable approach to QM/MM simulations. E. Lambros, F. Lipparini, G.A. Cisneros,

        F. Paesani. J. Chem. Theory Comput. 16, 7462 (2020). [link]

We present a new development in quantum mechanics/molecular mechanics (QM/MM) methods by replacing

conventional MM models with data-driven many-body (MB) representations rigorously derived from high-level QM

calculations. The new QM/MM approach builds on top of mutually polarizable QM/MM schemes developed for

polarizable force fields with inducible dipoles and uses permutationally invariant polynomials to effectively account

for quantum-mechanical contributions (e.g., exchange-repulsion, and charge transfer and penetration) that are

difficult to describe by classical expressions adopted by conventional MM models. Using MB-pol and MB-DFT,

which include explicit 2B and 3B terms fitted to reproduce the corresponding CCSD(T) and PBE0 2B and 3B

energies for water, we demonstrate a smooth energetic transition as molecules are transferred between QM and

MM regions. By effectively elevating the accuracy of both the MM region and the QM/MM interface to that of the

QM region, the new QM/MB-MM approach achieves an accuracy comparable to that obtained with a fully QM

treatment of the entire system.

145. Data-driven many-body models with chemical accuracy for CH4/H2O mixtures. M. Riera, A. Hirales, R. Ghosh,

        F. Paesani. J. Phys. Chem. B 124, 1127 (2020). [link]

We present a new development in quantum mechanics/molecular mechanics (QM/MM) methods by replacing

conventional MM models with data-driven many-body (MB) representations rigorously derived from high-level

QM calculations. Many-body potential energy functions (PEFs) based on the TTM-nrg and MB-nrg

theoretical/computational frameworks are developed from coupled cluster reference data for neat methane

and mixed methane/water systems. It is shown that that the MB-nrg PEFs achieve subchemical accuracy in

the representation of individual many-body effects in small clusters and enables predictive simulations from

the gas to the liquid phase. Analysis of structural properties calculated from molecular dynamics simulations

of liquid methane and methane/water mixtures using both TTM-nrg and MB-nrg PEFs indicates that, while

accounting for polarization effects is important for a correct description of many-body interactions in the liquid

phase, an accurate representation of short-range interactions, as provided by the MB-nrg PEFs, is necessary

for a quantitative description of the local solvation structure in liquid mixtures.