Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
Data science techniques in biomolecular force field
development
Ye Ding1,2, Kuang Yu3 and Jing Huang1,2
Abstract
Recent advances in data science are impacting the develop-
ment of classical force fields. Here we review some ideas and
techniques from data science that have been used in force
field development, including database construction, atom
typing, and machine learning potentials. We highlight how new
tools such as active learning and automatic differentiation are
facilitating the generation of target data and the direct fitting
with macroscopic observables. Philosophical changes on how
force field models should be built and used are also discussed.
It’s inspiring that more accurate biomolecular force fields can
be developed with the aid of data science techniques.
Addresses
1
Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences
and Biomedicine, Hangzhou, Zhejiang, 310024, China
2
Key Laboratory of Structural Biology of Zhejiang Province, School of
Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024,
China
3
Tsinghua Shenzhen International Graduate School, Tsinghua Uni-
versity, Shenzhen, Guangdong, 518055, China
Corresponding author: Huang Jing (huangjing@westlake.edu.cn)
Current Opinion in Structural Biology 2023, 78:102502
This review comes from a themed issue on Theory and Simulation/
Computational Methods (2023)
Edited by Turkan Haliloglu and Gregory A. Voth
For complete overview of the section, please refer the article collection -
Theory and Simulation/Computational Methods (2023)
Available online 30 November 2022
https://doi.org/10.1016/j.sbi.2022.102502
0959-440X/© 2022 Elsevier Ltd. All rights reserved.
Keywords
Data Science, Machine Learning, Force Field, Molecular Modeling,
Molecular Dynamics Simulation.
Introduction
Data science, a popular term in recent years, represents
the study of extracting knowledge and making inference
from data [1]. A variety of data science techniques have
been developed to curate, handle, and make use of
large-scale, heterogeneous data. The most successful
technique is probably machine learning (ML), in
particular deep learning (DL) that employs neural
networks (NNs). The development of data science is
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Structural Biology
also making a profound impact on how scientific
research is conducted [2]. People advocated that data
science is the fourth paradigm in scientific discovery [3].
Molecular mechanics force fields (FFs) are physics-
based computational models that connect the force
exerted on each atom with the coordinates of all atoms
in a given bsimulation system. Due to their central roles
in the molecular modeling and simulations of bio-
molecules, efforts are continuously made to increase
their accuracy, such as introducing more sophisticated
function forms and adopting better parametrization
strategies [4]. One of the key issues in biomolecular FF
development is transferability, or the ability of FF
models to generalize across different simulation envi-
ronments [5,6]. This is a non-trivial task due to the
significant difference between typical fitting data
(quantum mechanics (QM) calculations of small organic
molecules in vacuum) and the application scenarios
(biological macromolecules in the condensed phase).
Traditional biomolecular FFs are thus often considered
empirical, and their development and refinement is
largely a matter of trial and error. Many works are
dedicated to the systematic development of the bio-
molecular FFs with different algorithms [7].
With the ideas and techniques introduced by data science,
it might be possible to make FF development less
empirical and more data-driven. Established computa-
tional tools on data labeling, feature extraction, and model
fitting could be directly utilized (Figure 1). Furthermore,
new philosophies on how data should be treated and how
models should be constructed and evaluated might help.
In this manuscript, we will review the emerging efforts to
bring data science into biomolecular FF development.
These range from new fitting algorithms, new molecular
representation methods, to automatic differentiation
techniques. An important viewpoint in data science is that
data play the central role and should be made publicly
available, so we start by reviewing works on the con-
struction and sharing of FF-relevant datasets.
From providing FF parameters to making
data sets open access
Databases are the fundamental infrastructures in the era
of data science. Modern computational models require
larger and larger data sets for training and validation, and
Current Opinion in Structural Biology 2023, 78:102502
2 Theory and Simulation/Computational Methods (2023)

Figure 1

How data science techniques are transforming the development of empirical FFs. The importance of databases is emphasized, and new techniques such
as active learning are replacing rigid scan in the generation of fitting data. New optimization methods such as Bayesian inference and stochastic gradient
descent are introduced. Classical FF models (left panels) are released as text files containing parameters for different atom types, while in data science
trained models (right panels) are often provided as a whole and atom types can be replaced by continuous representations based on topological
connectivity.

high-quality databases facilitate the development of
computational models. A good example is AlphaFold [8],
whose success relies on the high-quality experimentally
resolved protein structures curated by the Protein Data
Bank (PDB) database [9]. FF development typically
requires large amounts of quantum mechanics-based
calculations using high-level correlation methods such
as the coupled cluster or at least the MP2 methods.
Traditional FF development works only publish the final
FF models but does not make the data used to fit the
models publicly accessible. With the general emphasis
on reproducibility and data availability, high-quality QM
databases for FF development have been established in
recent years [10].
We note that most existing QM databases at the
CCSD(T)/CBS level are intended for benchmarking
other QM methods such that only the geometries and
interactions of equilibrated structures are included. FF
development requires instead information on off-
equilibrated structures, or at least potential energy
scans along key degrees of freedom (DOFs). How to
generate representative off-equilibrated conformations
is a key challenge. Some QM databases start to provide
such information, for example, in the NCIAtlas database,
10-point scans along hydrogen bonding or dispersion
interaction distances are provided [11,12]. Specific data
sets for FF development have been released, most
notably a much larger database released by DEShaw
Research that contains the interaction energies on dimer
complexes of organic molecules at the CCSD(T)/CBS
level [13]. Off-equilibrated conformations of the dimer
complexes were generated by rigid scans along radial
intermolecular axis with initial structures extracted from
QM optimization and molecular dynamics (MD) trajec-
tory frames. A central dataset DES370K contains about
370,000 geometries evaluated with CCSD(T), and an
additional dataset DES5M contains about 5 million ge-
ometries evaluated with SNS-MP2, a ML approach
whose accuracy is equivalent to the coupled cluster level
[14]. Smith et al. created the ANI-1x and ANI-1ccx
datasets of small organic molecules with conformational
sampling along low-frequency normal modes [15].
Relevant off-equilibrated conformations are selected by
active learning and subjected to QM calculations. The
ANI-1x dataset contains 4.5 million conformations eval-
uated with the uB97x functional. Via an active learning
procedure using machine learning potentials trained
with ANI-1x, a smaller ANI-1ccx dataset was generated
with 0.5 million conformations evaluated with the
DLPNO-CCSD(T) method. In these two datasets only
C, H, O, and N elements are covered, while broader
coverage is also attempted [16]. Open access databases
accumulating high-quality QM calculation results would
greatly promote the application of various data science
techniques in FF parametrization. On the other hand,
the standardization of these emergent databases is
desired for the easy access of them [7].

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The validation and refinement of biomolecular FFs also
rely on condensed phase experimental data, such as
NMR scalar and dipolar couplings as well as molecular
liquid properties [17e20]. For example, the helical
content of (AAQAA)3 derived from NMR measurements
and its temperature dependence have systematically
driven protein FFs towards more accurate backbone
conformational sampling [17,21,22]. The Protein
Ensemble Database (PED) stored the structural
ensemble information of intrinsically disordered pro-
teins (IDPs), with about 212 protein entries annotated
with experimentally measured NMR, SAXS, or FRET
data [23]. More efforts to construct databases contain-
ing relevant experimental data would benefit the
development of biomolecular FFs.
Atom typing: from discrete types to
continuous embedding
Force field parameters can be generally divided into two
sets. One set includes per-atom parameters such as
partial charges and Van der Waals (VdW) parameters,
which describe the non-bonded interactions. The other
includes parameters to model bonded interaction terms
based on the topological connectivity of atoms in mo-
lecular fragments. The first step to employ an FF model
for a particular simulation system is atom typing, and the
assignment of both sets of parameters depends on the
atom types pre-defined in the FF. Atom typing is in
general difficult for small molecule ligands [24], while
for biomolecular FFs it also remains a question whether
it is necessary to introduce new atom types during the
FF development.
As the atom type is encoded by an atom’s topological
environment, mapping from the atom’s substructure to
FF parameters is feasible with a text-rich format for
chemical environment definition as illustrated by
Mobley et al. [25]. More generally, graph neural
network naturally provides the architecture for the
mimic of the topology environment, laying the foun-
dation of machine learning for atom types. Zhang pro-
posed to use topology adaptive graph convolutional
network (TAGCN) [26] for automatic atom typing
[27]. For each atom, the output of TAGCN is a prob-
ability density against all pre-defined atom types in a
certain FF. The network was trained to reproduce the
atom types assigned using the rule-based CGENFF
program [24,28], and achieved over 90% fidelity for
atomic typing problem in validation. To some extent,
atom typing in empirical FFs represents an abstraction
layer to reduce the dimensionality of the parameter
space [25]. We note that once atom types are deter-
mined, parameter assignment can also be aided by
machine learning [29,30]. While atom typing reduces
the searching space and enhances the model trans-
ferability, accuracy is inevitably compromised by the
finite discrete parameter space during optimization.
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Data science for force field development Ding et al. 3
Chodera and co-workers proposed Espaloma, a FF
model that discards atom typing and assigns parameters
with message-passing neural networks (MPNNs) [31].
Instead of mapping discrete atom types into FF pa-
rameters with tabulated functions, Espaloma uses
trained continuous functions to directly map the topo-
logical connectivity to bonded and non-bonded param-
eters. Determination of atomic partial charges is
complicated by the additional constraint that the total
charge should be an integer. To avoid the manual
redistribution of predicted charges, Espaloma predicts
atomic electronegativity and hardness and uses them to
compute the atomic charges analytically with Lagrange
multipliers to satisfy the constraint. This approach leads
to more accurate small molecule parameters as demon-
strated in the significant improvement in the binding-
free energy calculations of the Tyk2 ligand-protein
system [31].
Setting aside the function forms in FFs
Classical FFs model molecular interactions with
parametrized mathematical functions. The function
forms were empirically designed, which is extremely
successful as these function forms remain basically the
same for more than 50 years [32]. More sophisticated
function forms are introduced to account for polarization
effects through different formulas of polarizable FF
models [33,34]. In classical FFs, the curse of dimen-
sionality is avoided by a “divide-and-conquer” strategy
that decomposes the total energy to different interac-
tion terms, which effectively approximates the high-
dimensional potential energy surface to a series of 1-
or 2-dimensional subspaces. Theoretical advances in
data science point out that neural network-based ma-
chine learning can overcome the curse of dimensionality
when approximating high-dimensional functions
[35,36]. Recently, a variety of machine learning poten-
tials (MLPs) have been developed that discard the
empirical function forms in FFs and directly map the
atomic coordinates onto the potential energy and
forces [37].
MLPs can be generally classified into kernel-based or
neural network-based methods according to the ML
techniques employed (Figure 2). A determining factor
of their accuracy is how well the ML architecture can
preserve the physical symmetries of the simulation
system such as the rotational, translational, and per-
mutation invariance [38]. MLPs should also be size-
extensive, which means being transferable across sys-
tems with various sizes. The pioneering work by Behler
and Parrinello in 2007 proposed to construct the total
potential energy of a simulation system as the summa-
tion of atomic energies of individual particles [39]. Each
atomic energy is predicted by a NN that takes envi-
ronmental descriptors of the corresponding atom as
inputs. In Behler’s work, these input features are
Current Opinion in Structural Biology 2023, 78:102502
4 Theory and Simulation/Computational Methods (2023)
Figure 2
Illustrations on how the potential energy is determined by atom coordinates in (a) classical FFs, (b) kernel-based MLPs, (c) NN-based MLPs that utilize
atom-centered symmetry functions as environment descriptors, (d) the DP model with descriptors learned from embedding networks, and (e) MLPs with
descriptors learned by MPNN.
manually crafted to guarantee the translational and
rotational invariance. Smith et al. extended the defini-
tion of environment descriptors by including 3-body
interaction features, yielding the ANI series of models
that are widely used to model drug-like organic mole-
cules [40,16]. It’s also possible to replace the manually
designed environment descriptors with atomic features
learned by another embedding network. The embed-
ding NN and the fitting NN are trained together, and
different embedding strategies lead to different MLPs
such as the Deep Potential (DP) model [41] and the
SchNet model [42]. Following the popular philosophy of
data science, developers of the DP method provide full-
stack training and development tools to expand the
application scenarios for different users [43,44].
One consequence of setting aside the functional forms
is that separation of physically meaningful interaction
terms is not straightforward anymore. “Divide-and-
conquer” strategies for parametrize classical FFs are
thus no longer valid. Machine learning models are also
notorious for the extremely large number of parameters
to be determined, which implies that high-quality
MLPs require vast number of training data. To this
end, active learning is widely used in the construction of
MLPs [44,45]. In active learning, multiple MLP models
are trained at the same time and the variance of their
Current Opinion in Structural Biology 2023, 78:102502
predictions over a certain molecular conformation serves
as the criterion on whether this conformation should be
added to the training set. Using MD simulation for
conformational searching in active learning eventually
leads to simultaneous model training and application,
similar to the “on-the-fly” MD approach [46,47].
Moreover, active learning can be - and should be -
combined with more radical techniques to sample
conformational spaces as well as the chemical space.
While MLPs can achieve QM accuracy with the same
scaling of classical FFs, they are still computationally
much more expensive. Difficulties in the proper
handling of long-range interactions also limit their ap-
plications to highly heterogeneous systems [48,49]. To
explicitly include the non-local effects that are crucial
for the accurate modeling of long-range interactions,
improvement in current MLPs architectures is needed.
Unke et al. recently reported their efforts to construct a
MLP model for protein simulations by training on
“bottom-up” and “top-down” fragments of varying sizes
[50]. In general, accurate MLPs to simulate proteins
solvated in water or embedded in lipid bilayers are not
yet available. A more practical approach to use MLP for
biomolecular systems is via hybrid models. Compared
with the well-established QM/MM method, one
advantage of MLP/MM is that the electronic degrees of
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freedom in MLPs are implicitly integrated out. This
would simplify MD integration as there are consistent
DOFs between the MLP part and the classical MM part
in the model.
Both the ANI and the DP models have been used to
construct hybrid MLP/MM models for MD simulations
of biomolecules [51]. The whole simulation system is
described by a classical MM model, with a subset of
atoms modeled by an additional MLP model. The MLP
model can be trained to reproduce the difference in
atomic forces between QM calculations and the MM
model for the subset, or a subtraction of MM forces can
be performed during the simulation. We also note that
MLPs can be utilized to improve QM/MM calculations,
either as a correction to bridge low-level and high-level
QM methods [52,53] or as leverage to model the QM
influence on the QM/MM boundary [54].
Turbocharging FF development with
automatic differentiation
Development of biomolecular FFs typically involves
running MD simulations, from which thermodynamic
properties can be computed and compared with exper-
imental measurements. This requires analytical first
derivatives or even second derivatives (Hessians) of the
potential energy function. Furthermore, thermodynamic
properties can be leveraged to directly optimize FF
parameters through reweighting by taking the de-
rivatives with respect to particular FF parameters
[55,22]. Implementation of these derivatives is however
cumbersome, which limits the advanced optimization of
FFs. Fortunately, this is a common task in data science.
ML architectures, in particular the JAX, now provide
strong support to automatic differentiation and thus
remove the coding burden of derivative calculations.
Automatic differentiation allows agile FF construction
based on macroscopic observable values. Examples
include FF fitting targeting radial distribution functions
and specific folded conformations [56], and FF param-
etrization using hydration-free energies with automatic
differentiation [57]. In another study, a coarse-grained
protein FF is constructed using only RMSDs with
respect to targeted native folded conformational states
[58]. Aided by automatic differentiation, there are a
series of efforts towards the construction of end-to-end
differentiable molecular dynamics [59,60]. We do note
that automatic differentiation in DL bears the possible
issue of numerical instability, as the iterative utilization
of chain rules might induce gradient exploding or van-
ishing [61,62]. Recurrent neural networks are usually
included in ML architectures to confront the issue and
enhance the robustness of training models. Similar
considerations should be taken into account when
applying the automatic differentiation techniques in
MD simulations and FF development.
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Data science for force field development Ding et al. 5
What if there are multiple equally good FF
models?
During the development of biomolecular FFs, some-
times it’s possible to generate several parameter sets
when fitting to the QM calculations of model com-
pounds. These sets were usually subjected to MD
simulations of a few biomolecular systems, and one set
was selected empirically as the published final model.
With more sophisticated optimizers and the direct
fitting to condensed phase experimental data, it would
be common that several equally good FF models are
derived. For example, Lindorff and co-workers gener-
ated three different parameter sets when optimizing a
coarse-grained protein hydrophobicity scale (HPS)
model with Bayesian parameter-learning [63] and they
found that there was no significant difference between
these three models in describing the relevant IDP
properties. This would be even more common with
MLPs due to their much larger parameter spaces.
Interestingly, an understanding of the non-deterministic
nature of FF models would provide additional insights
on how these models should be used.
Data science provides a series of theoretical tools to
handle the uncertainties in computational models, such
as the Bayesian neural network and the committee
model. In the development of FFs, the uncertainties’
estimation is also important for its applications in
different scenarios [64e67]. Ceriotti and co-workers
derived a theoretical framework for the error estimation
of thermodynamic properties calculated from MD sim-
ulations considering the uncertainties of the FF models
employed [68]. Essentially, uncertainty propagation can
be performed for ensemble-averaged properties by
computing the uncertainty for each MD frame using the
committee model. Their work also demonstrated the
advantage to construct MLPs as add-ons of classical FFs
such that accuracy and generalization can be achieved at
the same time. A similarity to the well-established
ensemble learning method in ML should be noted [69].
Conclusions
Data science has changed the life of human beings in
the past decade, especially with the applications of deep
learning. To this end, it develops a variety of techniques
for the training and deployment of computational
models, which can help us develop better biomolecular
force fields. Scaling up these approaches to large, het-
erogeneous biomolecular systems is still a challenge due
to the difficulties in efficiently sampling the chemical
space and modeling long-range interactions. Attempts to
tackle these problems are ongoing, such as active
learning and large-scale pre-trained models, but good
solutions are yet to come. We expect accurate and
transferable MLPs or hybrid models using NNs for
proteins and nucleic acids would be available in the very
near future. Other data science techniques than those
Current Opinion in Structural Biology 2023, 78:102502
6 Theory and Simulation/Computational Methods (2023)
reviewed here might also be useful. For example,
continual learning can potentially change the way how
the transferability of FFs is assessed. Methods to handle
label noise and imbalanced datasets might also be
applicable to the robust optimization of FF models.
Together with applications in finding collective variables
for enhanced sampling [70], generating conformational
ensembles [71], or even directly accelerating the dy-
namics propagation [72], data science and machine
learning are revolutionizing the modeling and simulation
of biomolecular systems.
Conflict of interest statement
Nothing declared.
Data availability
Data will be made available on request.
Acknowledgments
This work was supported by the Zhejiang Provincial Natural Science
Foundation of China (Grant No. LR19B030001), the National Natural
Science Foundation of China (Grant No. 21803057, 32171247), and the
Shenzhen Science and Technology Innovation Commission (Grant
No: WDZC20200819115243002).
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