# Publications

• ### Capturing non-local through-bond effects when fragmenting molecules for quantum chemical torsion scans

Chaya D. Stern, Christopher I. Bayly, Daniel G. A. Smith, Josh Fass, Lee-Ping Wang, David L. Mobley, and John D. Chodera

Preprint ahead of publication: bioRxiv CC BY 4.0

Code accompanying the publication: openforcefield/fragmenter

We show how the Wiberg Bond Order (WBO) can be used to construct small molecule fragmentation schemes that will avoid disrupting the chemical environment around torsions. The resulting fragmentation scheme powers the QCSubmit tool used to fragment and inject small molecule datasets into the QCFractal computation pipeline for deposition into the QCArchive quantum chemistry archive the Open Force Field Initiative uses for constructing force fields, as well as powering bespoke torsion refitting for individual molecules.

• ### Improving Small Molecule Force Fields by Identifying and Characterizing Small Molecules with Inconsistent Parameters

Jordan Ehrman, Victoria T. Lim, Caitlin C. Bannan, Nam Thi, Daisy Kyu, and David Mobley

Preprint ahead of publication: chemRxiv CC BY 4.0

Code accompanying the publication: mobleylab/off-ffcompare

We present a pipeline for comparing the geometries of small molecule conformers optimized with different force fields. We aimed to identify molecules or chemistries that are particularly informative for future force field development because they display inconsistencies between force fields. We applied our pipeline to a subset of the eMolecules database, and highlighted molecules that appear to be parameterized inconsistently across different force fields. We then identified over-represented functional groups in these molecule sets. The molecules and moieties identified by this pipeline may be particularly helpful for future force field parameterization.

• ### Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning/molecular mechanics potentials

Dominic Rufa, Hannah Bruce Macdonald, Josh Fass, Marcus Wieder, Patrick Grinaway, Adrian Roitberg, Olexandr Isayev and John Chodera

Preprint ahead of publication: bioRxiv CC BY 4.0

Code accompanying the publication: choderalab/perses

This study combines a new generation of hybrid ML/MM potentials and a nonequilibrium perturbation approach to predict protein-ligand binding affinities. With this approach, a standard, GPU-accelerated MM alchemical free energy calculation can be corrected in a simple post-processing step to efficiently recover ML/MM free energies, while delivering a significant accuracy improvement with small additional computational effort. The authors show that it is possible to significantly reduce the error in absolute binding free energies with this new hybrid ML/MM approach ANI2xx/AMBER14SB/TIP3P on Tyk2 benchmarking system. The same set of FE calculations performed with OpenFF-1.0.0 instead of ANI2xx to model ligands achieves RMSE statistically indistinguishable from the Schrodinger JACS result for the tested system, which implies that we should expect even better results with the latest Parsley update (OpenFF-1.2.0).

• ### Benchmark Assessment of Molecular Geometries and Energies from Small Molecule Force Fields

Victoria T. Lim and David L. Mobley

Preprint ahead of publication: chemRxiv CC BY 4.0

Code accompanying the publication: mobleylab/benchmarkff

In this work, we aim to compare six force fields: GAFF, GAFF2, MMFF94, MMFF94S, SMIRNOFF99Frosst, and the openff-1.0.0 (Parsley) force field by focusing on small molecules (< 50 heavy atoms). On a dataset comprising over 26,000 molecular structures, we analyzed their force field-optimized geometries and conformer energies compared to reference quantum mechanical (QM) data. We show that most of these force fields are comparable in accuracy at reproducing gas-phase QM geometries and energetics, but that GAFF/GAFF2/Parsley do slightly better in reproducing QM energies and that MMFF94/MMFF94S perform slightly better in geometries. Parsley version OpenFF-1.0.0 shows considerable improvement over its predecessor SMIRNOFF99Frosst, while OpenFF-1.2.0 performs even better with accuracy comparable to other available general force fields. We identify particular outlying chemical groups for further force field improvement.

• ### Driving torsion scans with wavefront propagation

Yudong Qiu, Daniel G. A. Smith, Chaya D. Stern, Mudong Feng, Hyesu Jang, and Lee-Ping Wang

Preprint ahead of publication: chemRxiv CC BY 4.0

Published: The Journal of Chemical Physics 152:244116, 2020 [DOI]

Code accompanying the publication: lpwgroup/torsiondrive/

In this paper, we propose a systematic and versatile workflow called TorsionDrive to generate energy-minimized structures on a grid of torsion constraints by means of a recursive wavefront propagation algorithm, which resolves the deficiencies of conventional scanning approaches and generates higher quality QM data for force field development. The method is implemented in an open-source software package that is compatible with many QM software packages and energy minimization codes. The paper also describes integration with the MolSSI QCArchive distributed computing ecosystem.

• ### Binding thermodynamics of host-guest systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

David R. Slochower, Niel Henriksen, Lee-Ping Wang, John D. Chodera, David L. Mobley, and Michael K. Gilson

Preprint ahead of publication: chemRxiv CC BY 4.0

Published: Journal of Chemical Theory and Computation 15:6225, 2019 [DOI]

Code accompanying the publication: slochower/smirnoff-host-guest-manuscript

We evaluate the accuracy of SMIRNOFF99Frosst, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs and compare with matched calculations using two versions of GAFF. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.

• ### ChemPer: An Open Source Tool for Automatically Generating SMIRKS Patterns

Caitlin C. Bannan, David Mobley

Preprint ahead of publication: chemRxiv CC BY 4.0

Code accompanying the publication: MobleyLab/chemper

In this work, we present ChemPer – a new tool for generating SMIRKS patterns based on clustered fragments (i.e. bonds, angles, or torsions) which should be assigned the same force field parameter. We demonstrate the utility of ChemPer by clustering fragments based on a reference force field, and then regenerating those parameters starting with a simple set of alkanes, ethers, and alcohols.

• ### Systematic Optimization of Water Models Using Liquid/Vapor Surface Tension Data

Yudong Qiu, Paul S. Nerenberg, Teresa Head-Gordon, Lee-Ping Wang

Preprint ahead of publication: chemRxiv CC BY 4.0

Published: The Journal of Physical Chemistry B 123:7061, 2019 [DOI]

Code accompanying the publication: leeping/forcebalance

This work investigates whether experimental surface tension measurements, which are less sensitive to quantum and self-polarization corrections, are able to replace the usual reliance on the heat of vaporization as experimental reference data for fitting force field models of molecular liquids.

• ### Uncertainty quantification confirms unreliable extrapolation toward high pressures for united-atom Mie $\lambda$-6 force field

Richard A. Messerly, Michael R. Shirts, and Andrei F. Kazakov

Published: The Journal of Chemical Physics 149:114109, 2018 [DOI]

We demonstrate how Bayesian approaches can be used to estimate the reliability of predictions made with molecular mechanics force fields.

• ### Toward learned chemical perception of force field typing rules

Camila Zanette, Caitlin C. Bannan, Christopher I. Bayly, Josh Fass, Michael K. Gilson, Michael R. Shirts, John Chodera, and David L. Mobley

Preprint ahead of publication: chemRxiv CC BY 4.0

Published: Journal of Chemical Theory and Computation 15:402, 2019 [DOI]

Code accompanying the publication: openforcefield/smarty

Here, we introduce a proof of principle for automatically sampling chemical perception compared to traditional atom typed force fields and our SMIRNOFF format.

• ### Facile Synthesis of a Diverse Library of Mono-3-substituted β-Cyclodextrin Analogues

Kathryn Kellett, Brendan M. Duggan and Michael K. Gilson

Preprint ahead of publication: chemRxiv CC BY 4.0

Published: Supramolecular Chemistry 31:251, 2019 [DOI]

We show the facile synthesis of a library of diverse mono-3-substituted β-cyclodextrin analogues, that have the potential to be used to collect host-guest binding data to test and improve simulation force fields.

• ### Escaping atom types using direct chemical perception

David Mobley, Caitlin C. Bannan, Andrea Rizzi, Christopher I. Bayly, John D. Chodera, Victoria T Lim, Nathan M. Lim, Kyle A. Beauchamp, Michael R. Shirts, Michael K. Gilson, and Peter K. Eastman

Preprint ahead of publication: bioRxiv CC BY 4.0

Published: Journal of Chemical Theory and Computation 14:6076, 2018 [DOI] PMC6245550

This paper introduces the SMIRNOFF format in the context of traditional force fields, explains the development and validation of our new small molecule force field smirnoff99Frosst, and highlights some directions the initiative is headed.

• ### Toward Expanded Diversity of Host–Guest Interactions via Synthesis and Characterization of Cyclodextrin Derivatives

Kathryn Kellett, S. A. Kantonen, Brendan M. Duggan and Michael K. Gilson

Preprint ahead of publication: chemRxiv CC BY-NC-ND 4.0

Published: The Journal of Solution Chemistry 47:1597, 2018 [DOI]

This paper shows the synthesis of a mono-3-functionalized cyclodextrin and how cyclodextrin derivatives can effect the binding of guest molecules using 1D/2D NMR and ITC experiments.

• ### Approaches for Calculating Solvation Free Energies and Enthalpies Demonstrated with an Update of the FreeSolv Database

Guilherme Duarte Ramos Matos, Daisy Y. Kyu, Hannes H. Loeffler, John D. Chodera, Michael R. Shirts, and David L. Mobley

Preprint ahead of publication: bioRxiv CC BY 4.0

Published: Journal of Chemical Engineering Data 62:1559, 2017 [DOI] PMC5648357

Code accompanying the publication: mobleylab/freesolv

We review alchemical methods for computing solvation free energies and present an update (version 0.5) to the FreeSolv database of experimental and calculated hydration free energies of neutral compounds.

• ### Towards Automated Benchmarking of Atomistic Forcefields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive

Kyle A. Beauchamp, Julie M. Behr, Ariën S. Rustenburg, Christopher I. Bayly, Kenneth Kroenlein, and John D. Chodera

Preprint ahead of publication: arXiv arXiv-1.0

Published: Journal of Physical Chemistry B 119:12912, 2015 [DOI] PMC4667959

Code accompanying the publication: choderalab/LiquidBenchmark

Progress in forcefield validation and parameterization has been hindered by the availability of high-quality machine-readable physical property data for small organic molecules. We show how the NIST ThermoML dataset provides a solution to this problem, and demonstrate its utility in benchmarking the GAFF/AM1-BCC small molecule forcefield on neat liquid densities and static dielectric constants to uncover problems in the representation of low-dielectric environments.