pubs.acs.

org/jcim Article

Simulation Reveals the Chameleonic Behavior of Macrocycles

Daniel Sethio,† Vasanthanathan Poongavanam,† Ruisheng Xiong, Mohit Tyagi, Duc Duy Vo,
Roland Lindh, and Jan Kihlberg*
Cite This: J. Chem. Inf. Model. 2023, 63, 138−146 Read Online

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ABSTRACT: Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles
due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the
conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent
intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular
dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly.
Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations�standard state-of-
the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions
between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic
ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the
environment.

■ INTRODUCTION
Macrocycles are prominent among natural products and
the design of macrocyclic molecular chameleons remains an
important yet unresolved problem.
synthetic bioactive molecules, with vital roles in fields such In general, the conformational space populated by macro-
cycles is sampled well by different algorithms,14,15 but the
as supramolecular chemistry,1 artificial molecular machines,2
identification of the biologically relevant conformations, i.e.,
and drug discovery.3−5 Their unique properties originate from
solution- and/or target-bound conformations, remains a
the molecular-level preorganization of structural elements
formidable challenge.16,17 Recently, progress has been made
induced by macrocyclization. Predicting the conformational
for macrocyclic peptides which may form transannular
landscape of molecules is essential as it determines their
IMHBs.18−20 However, for nonpeptidic and semipeptidic
physical and biomolecular properties, but conformational
macrocycles, minimum energy conformations (MECs) identi-
analysis of macrocycles is complex and challenging.6,7 Reasons
fied by molecular mechanics using implicit solvation models
for this include that macrocycles often have a large number of
show large differences from the biologically relevant con-
degrees of freedom, form noncovalent transannular inter-
formations, while conformations resembling the biologically
actions such as intramolecular hydrogen bonds (IMHBs), and
relevant ones usually reside at ≥10−15 kcal mol−1 above the
that steric interactions and ring strain also influence macro-
cycle conformations. Large and flexible side chains further
increase the complexity of macrocycle conformational analysis, Received: August 29, 2022
in particular, as the flexibility of the ring may amplify the Published: December 23, 2022
overall flexibility.8,9 Nonbonded intramolecular interactions
between side chains and the macrocyclic ring allow macro-
cycles to behave as molecular chameleons8−13 a feature which
may provide major advantages in drug discovery.12 However,
© 2022 The Authors. Published by
American Chemical Society https://doi.org/10.1021/acs.jcim.2c01093
138 J. Chem. Inf. Model. 2023, 63, 138−146
Journal of Chemical Information and Modeling pubs.acs.org/jcim Article

Figure 1. (A) Structures of the macrocycles investigated in this study. (B) 1H NMR spectra of 1−5 in CDCl3 and DMSO-d6. Chemical shifts of
each of the three amide protons NH-I (red), NH-II (green), and NH-III (blue) are indicated.

MECs.16,17,21 Hence, this calls for the development of
computational protocols which correctly model the behavior
of macrocycles in a variety of environments such that the
predicted properties can guide the design of molecules for
specific purposes. The need for the prospective, property-based
design of macrocycles3,22 is further underlined by the
complexity of their synthesis.23
Inspired by the natural products hymenocardine,24 K-13,25
and OF4949-III,26 we designed macrocycles 1−5 that contain
an 18-membered macrocyclic ring with two side-chains (R and
Boc, Figure 1A).27 The R side-chain was chosen to allow the
139
formation of an intramolecular NH···π interaction (2−4) or a
hydrogen bond (5) with either of the adjacent amide bonds.
The chemical shifts of the three amide protons of 1−5 indicate
major structure- and environment-dependent conformational
differences between 1−5 (Figure 1B, Supplementary Figures
S1−S12, Tables S1 and S2). For instance, the chemical shift of
NH-I shows a large variation between 1−5 in a nonpolar
environment (CDCl3, ε = 4.8) but not in the polar one
(DMSO-d6, ε = 46.7). As chemical shifts are sensitive to
molecular structure and dynamics,28−32 macrocycles 1−5
constitute an ideal system for the development and assessment
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Journal of Chemical Information and Modeling
of computational protocols to predict macrocycle conforma-
tions. Herein, we report our successful efforts to this end.
Molecular dynamics (MD) simulations, followed by DFT
optimization of the generated conformational ensembles,
allowed the correct prediction of solvent-dependent dynamic
intramolecular interactions and of a conformational switch of
the ring in the series of macrocycles.
■ METHODS
Monte Carlo Conformational Sampling (MCMM). The
2D structures of the designed macrocycles 1−5 were built with
correct stereochemistry using Maestro from the Schrödinger
suite.33 The resulting initial structures were directly used as
input for the Monte Carlo Multiple Minimum (MCMM)
Conformational Sampling using implicit solvation models.
The MCMM conformational samplings were conducted
using the Macromodel software as implemented in the
Schrödinger Suite version 2020-4.34 The MCMM sampling35
was done in both polar and nonpolar environments as
represented by dimethyl sulfoxide (DMSO, ε = 46.7) and
chloroform (CHCl3, ε = 4.8) using the OPLS3e force field.36
Briefly, the conformational space of each macrocycle in each of
the two solvents was stochastically explored by extended
sampling of the torsional angles. The following settings were
used for the study: energy window (10 kcal/mol), elimination
of duplicate conformer threshold (RMSD, 0.75 Å), the total
number of iterations (10,000 steps), and force field [Polak-
Ribière Conjugate Gradient (PRCG) in combination with the
OPLS3e force field36]. For each kept unique conformation
(within the 10 kcal/mol window, RMSD >0.75 Å relative to
conformations identified earlier in the sampling), a degeneracy
index was assigned, indicating how many times identical
conformations were found in the iterative sampling. Finally, the
10 conformations that had the highest degeneracy index were
selected. The MC protocol used the MEC from the MCMM
calculations for each compound in each of the two solvents to
calculate the chemical shifts of NH-I, NH-II, and NH-III.
Subsequently, all conformations (10 per compound and
solvent) were subjected to DFT-based geometry optimization
as described below.
MD Simulations. All MD simulations for compounds 1−5
were performed using the Amber18 package37 utilizing the
General Amber Force Field (GAFF).38 The initial geometry
for 1−5 was taken from the lowest energy conformer as
obtained from the MCMM calculation. Charges for atoms
were assigned based on the electrostatic potential (ESP) fitting
using the RESP procedure39 as implemented in Antechamber
software.40 The ESP calculation was carried out at the B3LYP/
cc-pVTZ level of theory, using the Gaussian 16 Rev. C.01
software.41 Solvent molecules (CHCl3 or DMSO) were added
to the macrocycles with 30 Å buffering distance between the
edges of the truncated cubic box. Subsequently, the tleap tool42
from the Amber package was used to build topology and
coordinate files for carrying out the MD calculations. Initially,
energy minimization was carried out in two steps. First, the
steepest descent method was used to minimize the energy with
respect to the hydrogen atom positions with a maximum of
1000 steps, whereas heavy atoms were constrained. Second,
the conjugate gradient method with 2000 steps was used to
minimize the whole solute−solvent system. Subsequently, the
system was heated from 0 to 300 K at a constant volume for
200 ps. After the thermalization process, the system was
equilibrated at constant temperature (300 K) and pressure (1
140
pubs.acs.org/jcim Article
bar) using the Berendsen coupling algorithm43 for another 500
ps MD simulation. Finally, the MD production run was
performed for 50 ns for each compound in the two solvents.
The SHAKE algorithm44 was used to constrain all bonds
involving hydrogen atoms. Snapshots were collected every 10
ps from the 50 ns simulation, resulting in a total of 5000
snapshots for further analysis for each compound and solvent.
A nonbiased selection of 10 of the 5000 snapshots provides a
representative subset with minimal likelihood of not including
the major conformation and several high-energy conforma-
tions. Every 500th conformation was therefore chosen, and the
energy was calculated at the B3LYP/6-311++G(2d,p) level of
theory. The MD protocol used the MEC out of these 10
conformations for each compound in each of the two solvents
to calculate the chemical shifts of NH-I, NH-II, and NH-III.
Subsequently, all conformations (10 per compound and
solvent) were subjected to DFT-based geometry optimization
as described below.
Trajectory Analysis. The conformational change of
macrocycles was followed through RMSD, inter- and intra-
molecular hydrogen bonding, and NH···π interactions utilizing
the cpptraj tool.45 The RMSD values were calculated with
respect to the initial geometry, while the NH···π interactions
were evaluated by measuring the distance between the N atom
to the center of the phenyl ring. The flexibility of the dipeptide
of the macrocyclic ring was monitored through the change of
the two dihedral angles ϕ and ψ (see the Supporting
Information).
Geometry Optimization (DFT). The 10 conformations
obtained from the MCMM calculations and the MD
simulations for each compound in each of the two solvents
were further optimized at the DFT level using the Gaussian 16
Rev. C.01 program.41 To find a reliable and practical method
for describing nonbonded interactions, several DFT func-
tionals and basis sets have been tested. The dispersion-
corrected functionals such as B3LYP46,47 augmented with the
semiempirical Grimme’s D3 dispersion corrected,48 M06-2X,49
and wB97X-D50 functionals have been tested together with
Pople’s 6-31+G(d,p)51 and 6−31++G(d,p)52 as well as
Dunning’s cc-pVDZ and cc-pVTZ basis sets.53,54 The M06-
2X functional in combination with Pople’s 6-31 + G(d,p) was
chosen as the best compromise to accurately describe
nonbonded interactions as suggested by Willoughby and co-
workers.55 The implicit polarizable continuum model of
Tomasi and co-workers was used to account for CHCl3 and
DMSO solvation effects.56 To ensure the optimized geometry
corresponding to a minimum on the potential energy surface,
vibrational frequency calculations were conducted at the same
level of theory. The MECs for each compound in each of the
two solvents were used to calculate the chemical shifts of NH-
I, NH-II, and NH-III in the MC:DFT and MD:DFT protocols.
All 10 conformations were used for the MC:DFTens and
MD:DFTens protocols.
NMR Chemical Shift Calculations. NMR chemical
shielding(s) calculations were calculated at the B3LYP/6-
311++G(2d,p) level of theory utilizing the Gauge-Independent
Atomic Orbital (GIAO) method.57 The triple-ξ polarized
quality augmented with the diffuse functions basis set is
necessary to obtain accurate NMR shielding tensor values.58
The NMR chemical shifts are obtained by subtracting the
chemical shielding tensor value of the reference compound
with the chemical shielding tensor value of the molecule of
interest (δ = σref − σ). Tetramethyl silane (TMS) was used as a
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reference compound for calculating the GIAO tensor of 1H (DMSO) were developed. Second, the robustness of the
NMR. protocols was evaluated by a comparison between theoretical
Model Evaluation. Prediction of relevant conformations and experimental results, i.e., the chemical shifts of protons
was evaluated in the following scenario, if the minimum energy NH-I, NH-II, and NH-III (Figure 1),273JH,H scalar coupling
conformer (MEC) is representative (or not) of the constants, and nuclear Overhauser effects (NOEs) of protons
conformations populated by the compound in different within the macrocyclic ring of 1−5. For the first part, six
environments. different protocols were explored to generate representative
Interproton Distances (NOEs). To obtain quantitative conformations of 1−5 (Table 1). Initial conformational
inter-proton distances, seven 1H,1H-NOESY experiments were sampling was performed either by the MCMM method,
evaluated with increasing mixing times ranging from 50 to 350 which incorporated an implicit solvation model, or by the more
ms. Experiments were recorded in random order to counteract computationally intensive unrestrained-MD simulations using
systematic errors. Spectra were acquired with 1024 × 2048 an explicit solvation model. These sampling methods are based
complex points (F1 × F2) and a spectral width of 6410 Hz. on state-of-the-art force fields and are denoted MC and MD,
The recycle relaxation delay (d1) was set to 3 s. Deuterium respectively, when their MECs are used as representative
signals of CDCl3 and DMSO-d6 were used for the lock signal. conformations. An improved level of conformational sampling
Diagonal and cross peaks were integrated for all mixing times was established by ab initio DFT molecular geometry
and individual NOE intensities taken as the absolute integral optimization of ten conformations selected from the
were normalized according to established MC and MD ensembles (cf. Methods). We denote
the use of the MECs from these optimized ensembles
|cross peakij × cross peakij| protocols MC:DFT and MD:DFT. Finally, the full ensembles
=2
norm, ij
|diagonal peaki × diagonal peakj| consisting of ten conformations for each macrocycle constitute
(1) the MC:DFTens and MD:DFTens protocols, respectively. We
per mixing time, respectively. A minimum of four normalized note that the MECs of the MC:DFT protocol were used as a
intensities, ηnorm, for consecutive mixing times describing a seed for subsequent MD conformational exploration.
linear initial build-up with R2 ≥ 0.95 were used to determine Protocol for Finding Relevant Conformations of
the build-up rate σij. Build-up rates of locked-in-distance Macrocycles. As expected from previous reports,16,17 the
protons were used as distance reference (e.g., geminal protons: MECs predicted by MC sampling were not representative of
1.78 Å). Distances were calculated according to the solution conformations of 1−5 (Table 1, protocol MC,
Supplementary Figure S13). The MC:DFT protocol provided
1/6
ij yz a significant improvement in the correlation between predicted
rij = rref jjjj ref zz
zz and observed chemical shifts for the MECs in chloroform, but
j z
k ij { (2) not in DMSO (Table 1, Figure 2A). Inspection of the MECs
from this protocol indicated that the shielding and deshielding
where rij is the resulting distance between protons i and j, rref is
of NH-I observed for compounds 3 and 5 in chloroform
the fixed distance of the reference proton pair, σref is the build-
(Figure 1B) originated from the formation of an intramolecular
up rate of the used reference protons, and σij is the build-up
NH···π interaction or hydrogen bond with the adjacent R
rate of the protons of interest using normalized NOE
intensities.59 phenyl and 2-pyridyl groups, respectively. The IMHB was
maintained in implicit DMSO, providing one explanation for
■ RESULTS AND DISCUSSION
Study Design. First, protocols to identify the conforma-
the poor correlation in this solvent. Averaging of chemical
shifts calculated from the DFT-optimized conformational
ensembles within an energy window of 5, 10, 15, and 20
tional dynamics of macrocycles as a function of the polarity of kcal mol−1 did not provide any major improvement (Table 1,
the environment, i.e., apolar (chloroform) versus polar protocol MC:DFTens, Supplementary Figure S14). An
implicit solvation model thus failed to reproduce solvation
Table 1. Protocolsa Evaluated for Conformational Sampling effects in the polar solvent DMSO, while it provided a good
of Macrocycles 1−5 and the Quality of the Models for the representation of the conformations adopted in an apolar
Prediction of the Chemical Shifts of NH-I, NH-II, and NH- environment.60,61 We, therefore, turned to unrestrained MD
IIIb simulations in explicit solvents to capture the solvation effects
CHCl3 (ε 4.8) DMSO (ε 46.7) on the conformations of 1−5.
a 2 The MECs of protocol MC:DFT, all had the R side-chain
protocol solvation model R RMSE R2 RMSE
oriented equatorially on the macrocyclic ring (Supplementary
MC implicit 0.13 1.16 −0.32 2.72 Figure S15), but the ensembles also contained conformations
MC:DFT implicit 0.81 0.57 0.0003 2.41 in which both amide bonds within the macrocycle had been
MC:DFTens implicit 0.91 0.68 −0.002 2.17 rotated in the plane, thereby placing R axially (Figure 2B). In
MD explicit 0.29 0.93 0.02 1.82
chloroform, conformations that had R axially had energies
MD:DFT explicit 0.88 0.66 0.63 1.26
higher than that of the MEC (>3−22 kcal mol −1 )
MD:DFTens explicit 0.97 0.45 0.59 0.95
(Supplementary Table S3), suggesting the equatorial con-
a formations as starting points for the MD simulations. To
MC: Monte Carlo Multiple Minimum; MD: Molecular Dynamics;
DFT: Density Functional Theory. The subscript “ens” indicates that understand whether these two minima are connected in the
the model is based on the average of the chemical shifts of the potential energy surfaces, we performed MD simulations at
conformational ensemble within 10 kcal mol−1 of the MEC. bThe increasing temperatures for compound 5 in DMSO, since 5
quality of the protocols are described by the Pearson’s correlation may be particularly prone to remain in a local minimum due to
coefficient (R2) and the root mean square error (RMSE, δ, ppm). the formation of an IMHB between the pyridyl group and NH-
141 https://doi.org/10.1021/acs.jcim.2c01093
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Figure 2. (A) Correlation between predicted and experimental 1H chemical shifts in chloroform and DMSO for compounds 1−5. The top two
panels show the correlations obtained for the MECs from protocol MC:DFT, the middle panels show the correlations obtained for the MECs from
protocol MD:DFT, while the two panels at the bottom show the correlations based on the MD:DFTens ensemble within 10 kcal mol−1 of the MEC.
R2: the Pearson correlation coefficient; RMSE: root-mean-square-error (ppm). (B) Schematic description of the conformational interconversion of
the macrocyclic ring that results in the reorientation of the R side-chain from and equatorial to an axial position.

R equatorial as suitable starting points for the MD simulations

Figure 3. Distance between (A) the nitrogen atom of NH-I and the
center of the R phenyl ring and (B) the nitrogen atom of NH-I and
the nitrogen atom of the pyridyl moiety in the MD trajectories of
compounds 3, 4, and 5, respectively, in DMSO and CHCl3. Distance
range for the formation of a NH···π shielding (2.9−3.6 Å) and non-
negligible IMHB (1.5−2.5 Å) are highlighted in green.
I. These simulations showed a transition from the axial to the
equatorial orientation of the R side-chain at 500 K
(Supplementary Figure S16), revealing conformations having
142
also in DMSO.
The MECs from the MD protocol provided poor
correlations to the experimental chemical shifts both in
chloroform and DMSO (Table 1, Supplementary Figure
S17) probably due to an inadequate description of the
solvation effects by the force field. However, the analysis of
the frequency of hydrogen bonds revealed that IMHBs found
in chloroform were broken up in DMSO and that the amide
protons of 1−5 were hydrogen-bonded to DMSO (Supple-
mentary Figures S18 and S19). DFT optimization, protocol
MD:DFT, of the conformations, including the hydrogen-
bonded DMSO molecules, led to a major improvement of the
chemical shift correlations for the MECs both in chloroform
and in DMSO (Table 1, Figure 2A). Lastly, the use of the <10
kcal mol−1 ensembles of protocol MD:DFTens provided even
better models in both solvents (Table 1, Figure 2A,
Supplementary Figure S20) than the MD:DFT protocol.
The 3JH,H coupling constants for the protons in the macrocyclic
ring of 1−5 were used to further validate the protocols.
Encouragingly, the simulated coupling constants for the MECs
of protocol MD:DFT agreed well with the experimentally
determined 3JH,H values both in chloroform and in DMSO
(Supplementary Tables S4 and S5). This was also the case for
the optimized MECs of the MC:DFT sampling protocol in
chloroform, but not in DMSO.
Validation of the Ability of the MD:DFTens Protocol
To Predict Molecular Chameleons. The MD simulations
suggested that the phenyl ring of phenylalanine 3 formed a
significantly larger proportion of NH···π interactions with NH-
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Figure 4. (A) RMSD of the heavy atoms of the macrocyclic ring of compounds 1, 3, and 5 calculated from the MD trajectories in explicit
chloroform and DMSO. Representative conformations having the ring in states 1 and 2 have been indicated for each compound. (B) Structures of
the state 1 and 2 conformations adopted in DMSO. The 3JH,H coupling constants and NOEs for protons NH-I and Ha−Hc provide key information
that differentiates the two states. Coupling constants calculated for the state 1 and 2 conformations of the MEC from the MD:DFT protocol of
compound 3 in DMSO have been included in the figure. Coupling constants determined by NMR spectroscopy in DMSO-d6 for 3 have been
inserted in the box for comparison.

I in chloroform than for homophenylalanine 4 (Figure 3A).
Experimental support is provided by the large shielding of NH-
I of 3 in chloroform as compared to 4 (Figure 1). For
compound 5, NH-I forms an IMHB to the pyridine moiety
with high frequency in chloroform (Figure 3B), as expected
from the large deshielding of NH-I observed in the NMR
spectrum of 5 (Figure 1). These nonbonded interactions are
disrupted in the MD simulations of 3 and 5 in explicit DMSO
(Figure 3), in excellent agreement with that shielding/
deshielding of NH-I are not observed in DMSO (Figure 1).
The MD trajectories of compounds 1−5 in the two
environments also suggested that the macrocyclic ring
populates a few major conformations (Supplementary Figure
S21). For 1, 3, and 5, the ring appeared to switch between two
143
major conformations with 1 showing this behavior both in
chloroform and DMSO, while 3 and 5 displayed it only in
DMSO (Figure 4A). The conformations from protocol
MD:DFTens of 1, 3, and 5 revealed that the two conforma-
tional states originated from an in-plane rotation of the NH-I
amide bond (Figure 4B). This places NH-I and NH-II on
opposite faces of the macrocycle in state 1 and on the same
face in state 2. The DFT-optimized MECs for the three
macrocycles belong to state 1 both in chloroform and in
DMSO. In chloroform, the second state of 1 was found to
reside >20 kcal mol−1 above the MEC, i.e. the population of
state 2 is negligible for 1 just as suggested by the MD
simulations for 3 and 5 (Supplementary Table S6). However,
in DMSO, the relative population of state 2 was indicated to be
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Journal of Chemical Information and Modeling
significant for all three macrocycles due to the coordination of
a DMSO molecule by NH-I and NH-II (Figure 4).
The 3JH,H coupling constants and NOEs for protons NH-I,
Ha, and Hb support the solvent-induced switch of the
macrocyclic ring (Figure 4). In chloroform, the experimentally
determined coupling constants between NH-I and the two
adjacent methylene protons agree very well with the coupling
constants predicted for state 1 (Supplementary Table S7),
providing experimental support for the population of only this
state in an apolar environment. In DMSO, the 3JNH‑I‑Hb
coupling constant determined by NMR spectroscopy lies in
between the ones calculated for the state 1 and 2
conformations for the three macrocycles (exemplified for 3
in Figure 4B, Table S8). This is also the case for 3JNH‑I‑Ha for 3,
whereas line-broadening prevented analysis for 1 and 5. The
coupling constants thus support that 1, 3, and 5 interconvert
rapidly between the state 1 and 2 conformations in DMSO.
NOESY confirmed the existence of the solvent-induced
conformational switch. Specifically, NH-I displays an observ-
able NOE only to one of the adjacent methylene protons (Ha)
in chloroform, but to both methylene protons in DMSO
(Figure 4B, Supplementary Table S9, Figures S22−S27). In
addition, the distance between NH-I and methine proton Hc
was determined to be longer in DMSO than in chloroform for
1, 3, and 5 as would be expected from the population of both
states in DMSO (Supplementary Table S9).
■ CONCLUSIONS
Herein, we have reported the successful prediction of the
conformational ensembles of a series of macrocycles in
environments that differ in polarity and hydrogen bonding
capacity. Monte Carlo conformational sampling in implicit
solvent, followed by DFT optimization, provided an excellent
description of the conformations populated in chloroform, but
not so in the polar DMSO. The lack of predictivity of implicit
solvent models in polar environments has been noted earlier
for macrocycles16,17,21 and was comprehensively illustrated in a
most recent study of linear peptides.62 However, we found that
MD simulations using explicit solvation followed by DFT
optimization described the conformations of the macrocycles
correctly in both environments. These observations indicate
that hydrogen bonding dictates the use of explicit solvent
models for correct predictions in polar solvents.
Our MD simulations suggested that DMSO induced a
conformational switch of the macrocyclic ring, while chloro-
form did not. Determination of coupling constants and NOEs
by NMR spectroscopy verified this dynamic, solvent-depend-
ent conformational flexibility. As the solvent-dependent
formation of intramolecular NH···π and IMHB interactions
between side-chains and the macrocyclic backbone were also
correctly predicted, we conclude that MD simulations,
followed by DFT optimization, can be used for the prospective
design of molecular chameleons. Molecular chameleonicity is
of major interest in drug discovery as it allows compounds to
display high aqueous solubility and high cell permeability,
properties that are highly desired but often difficult to engineer
into a drug candidate.
■ ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jcim.2c01093.
144
pubs.acs.org/jcim Article
Tables and figures with calculated data and NMR data;
and experimental procedures for the synthesis of 5
(PDF)
Excel showing SMILES of compounds 1−5 (XLSX)
Excel showing chemical shifts statistics (XLSX)
RMSD analysis (XLSX)
Dihedral angle analysis (XLSX)
Distance and IMHB analysis (XLSX)
■ AUTHOR INFORMATION
Corresponding Author
Jan Kihlberg − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden; orcid.org/0000-
0002-4205-6040; Email: jan.kihlberg@kemi.uu.se
Authors
Daniel Sethio − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden; orcid.org/0000-
0002-8075-1482
Vasanthanathan Poongavanam − Department of Chemistry
− BMC, Uppsala University, SE-751 23 Uppsala, Sweden;
orcid.org/0000-0002-8880-9247
Ruisheng Xiong − Department of Chemistry − BMC,
Uppsala University, SE-751 23 Uppsala, Sweden
Mohit Tyagi − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden
Duc Duy Vo − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden
Roland Lindh − Department of Chemistry − BMC, Uppsala
University, SE-751 23 Uppsala, Sweden; orcid.org/0000-
0001-7567-8295
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jcim.2c01093
Author Contributions
†
D.S. and V.P. contributed equally.
Notes
The authors declare no competing financial interest.
MD trajectories and molecular topology parameter files from
the MD simulations are available free of charge at https://doi.
org/10.5281/zenodo.7022549. Python scripts used for auto-
mation of the calculation of chemical shifts and optimized
geometries are available free of charge at https://github.com/
danielquantum/NMR-Macrocycles.
■ ACKNOWLEDGMENTS
This work was funded by grants from the Swedish Research
Council [Grants No. 2021-04747 (JK) and 2020-03182 (RL)].
Computations were performed on resources provided by the
Swedish National Infrastructure for Computing (SNIC) under
project numbers SNIC 2021/22-244, SNIC 2021/22-125,
SNIC 2021/22-860, and SNIC 2019/3-295. This study made
use of the NMR Uppsala infrastructure, which is funded by the
Department of Chemistry - BMC and the Disciplinary Domain
of Medicine and Pharmacy. The authors are grateful to Marjan
Khamesian, N. Arul Murugan, and Máté Erdélyi for their
valuable contributions and discussions.
■ REFERENCES
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