13 research outputs found
Effective Fragment Potential Method for HâBonding: How To Obtain Parameters for Nonrigid Fragments
Accuracy of the effective
fragment potential (EFP) method was explored
for describing intermolecular interaction energies in three dimers
with strong H-bonded interactions, formic acid, formamide, and formamidine
dimers, which are a part of HBC6 database of noncovalent interactions.
Monomer geometries in these dimers change significantly as a function
of intermonomer separation. Several EFP schemes were considered, in
which fragment parameters were prepared for a fragment in its gas-phase
geometry or recomputed for each unique fragment geometry. Additionally,
a scheme in which gas-phase fragment parameters are shifted according
to relaxed fragment geometries is introduced and tested. EFP data
are compared against the coupled cluster with single, double, and
perturbative triple excitations (CCSDÂ(T)) method in a complete basis
set (CBS) and the symmetry adapted perturbation theory (SAPT). All
considered EFP schemes provide a good agreement with CCSDÂ(T)/CBS for
binding energies at equilibrium separations, with discrepancies not
exceeding 2 kcal/mol. However, only the schemes that utilize relaxed
fragment geometries remain qualitatively correct at shorter than equilibrium
intermolecular distances. The EFP scheme with shifted parameters behaves
quantitatively similar to the scheme in which parameters are recomputed
for each monomer geometry and thus is recommended as a computationally
efficient approach for large-scale EFP simulations of flexible systems
Ground-State Charge Transfer: LithiumâBenzene and the Role of HartreeâFock Exchange
Most
approximations to the exchange-correlation functional of KohnâSham
density functional theory lead to delocalization errors that undermine
the description of charge-transfer phenomena. We explore how various
approximate functionals and charge-distribution schemes describe ground-state
atomic-charge distributions in the lithiumâbenzene complex,
a model system of relevance to carbon-based supercapacitors. To understand
the trends, we compare HartreeâFock (HF) and correlated post-HF
calculations, confirming that the HOMOâLUMO gap is narrower
in semilocal functionals but widened by hybrid functionals with large
fractions of HF exchange. For semilocal functionals, natural bond
orbital (NBO) and Mulliken schemes yield opposite pictures of how
charge transfer occurs. In PBE, for example, when lithium and benzene
are <1.5 Ă
apart, NBO yields a positive charge on the lithium
atom, but the Mulliken scheme yields a negative charge. Furthermore,
the partial charges in conjugated materials depend on the interplay
between the charge-distribution scheme employed and the underlying
exchange-correlation functional, being critically sensitive to the
admixture of HF exchange. We analyze and explain why this happens,
discuss implications, and conclude that hybrid functionals with an
admixture of about one-fourth of HF exchange are particularly useful
in describing charge transfer in the lithiumâbenzene model
TripletâTriplet Coupling in Chromophore Dimers: Theory and Experiment
Knowledge of triplet
state energies and tripletâtriplet
(TâT) interactions in aggregated organic molecules is essential
for understanding photochemistry and dynamics of many natural and
artificial systems. In this work, we combine direct phosphorescence
measurements of triplet state energies, which are challenging due
to the spin-forbidden nature of respective transitions and applicable
to only a limited number of systems, with quantum chemical computational
tools that can provide valuable qualitative and quantitative information
about triplet states of interacting molecules. Using hexatriene, protoporphyrin,
pheophorbide, and chlorophyll dimers as model systems, we demonstrate
a complicated dependence of TâT coupling on a relative orientation
of chromophores, governed by a nodal structure of overlapping electronic
wave functions, that modulates interpigment interactions by orders
of magnitude. It is also shown that geometrical relaxation of the
triplet state is one of the critical factors for predictive modeling
of TâT interactions in molecular aggregates
Quantifying the Nearly Random Microheterogeneity of Aqueous <i>tert</i>-Butyl Alcohol Solutions Using Vibrational Spectroscopy
The microheterogeneous structure of aqueous tert-butyl alcohol (TBA) solutions is quantified by combining experimental,
simulations, and theoretical results. Experimental Raman multivariate
curve resolution (Raman-MCR) CâH frequency shift measurements
are compared with predictions obtained using combined quantum mechanical
and effective fragment potential (QM/EFP) calculations, as well as
with molecular dynamics (MD), random mixture (RM), and finite lattice
(FL) predictions. The results indicate that the microheterogeneous
aggregation in aqueous TBA solutions is slightly less than that predicted
by MD simulations performed using either CHARMM generalized force
field (CGenFF) or optimized parameters for liquid simulations all
atom (OPLS-AA) force fields but slightly more than that in a self-avoiding
RM of TBA-like molecules. The results imply that the onset of microheterogeneity
in aqueous solutions occurs when solute contact free energies are
about an order of magnitude smaller than thermal fluctuations, thus
suggesting a fundamental bound of relevance to biological self-assembly
Dispersion Interactions in QM/EFP
The
dispersion energy term between quantum-mechanical (QM) and
classical (represented by effective fragment potentials, EFP) subsystems
is developed and implemented. A new formulation is based on long-range
perturbation theory and uses dynamic polarizability tensors of the
effective fragments and electric field integrals and orbital energies
of the quantum-mechanical subsystem. No parametrization is involved.
The accuracy of the QMâEFP dispersion energy is tested on a
number of model systems; the average mean unsigned error is 0.8 kcal/mol
or 13% with respect to the symmetry adapted perturbation theory on
the S22 data set of noncovalent interactions. The computational cost
of the dispersion energy computation is low compared to the self-consistent
field calculation of the QM subsystem. The dispersion energy is sensitive
to the level of theory employed for the QM part and to the electrostatic
interactions in the system. The latter means that the dispersion interactions
in the QM/EFP method are not purely two-body but have more complex
many-body behavior
Accurate Prediction of Noncovalent Interaction Energies with the Effective Fragment Potential Method: Comparison of Energy Components to Symmetry-Adapted Perturbation Theory for the S22 Test Set
Noncovalent interactions play an important role in the
stabilization
of biological molecules. The effective fragment potential (EFP) is
a computationally inexpensive ab initio-based method for modeling
intermolecular interactions in noncovalently bound systems. The accuracy
of EFP is benchmarked against the S22 and S66 data sets for noncovalent
interactions [JurecĚka, P.; SĚponer, J.; CĚernyĚ,
J.; Hobza, P. <i>Phys. Chem. Chem. Phys.</i> <b>2006</b>, <i>8</i>, 1985; RĚezaĚcĚ, J.; Riley,
K. E.; Hobza, P. <i>J. Chem. Theory Comput.</i> <b>2011</b>, <i>7</i>, 2427]. The mean unsigned error (MUE) of EFP
interaction energies with respect to coupled-cluster singles, doubles,
and perturbative triples in the complete basis set limit [CCSDÂ(T)/CBS]
is 0.9 and 0.6 kcal/mol for S22 and S66, respectively, which is similar
to the MUE of MP2 and SCS-MP2 for the same data sets, but with a greatly
reduced computational expense. Moreover, EFP outperforms classical
force fields and popular DFT functionals such as B3LYP and PBE, while
newer dispersion-corrected functionals provide a more accurate description
of noncovalent interactions. Comparison of EFP energy components with
the symmetry-adapted perturbation theory (SAPT) energies for the S22
data set shows that the main source of errors in EFP comes from Coulomb
and polarization terms and provides a valuable benchmark for further
improvements in the accuracy of EFP and force fields in general
Phase Behavior of Drug-Hydroxypropyl Methylcellulose Amorphous Solid Dispersions Produced from Various Solvent Systems: Mechanistic Understanding of the Role of Polymer using Experimental and Theoretical Methods
The
vast majority of studies evaluating amorphous solid dispersions
(ASDs) utilize solvent evaporation techniques as the preparation method.
However, the impact of the solvent/cosolvent system properties on
the polymer conformation and the phase behavior of the resultant drug/polymer
blends is poorly understood. Herein, we investigate the influence
of solvent properties on the phase behavior of ASDs containing itraconazole
(ITZ) and hydroxypropylmethyl cellulose (HPMC) prepared using spin
coating from binary/ternary cosolvent systems containing alkyl alcohols,
dichloromethane (DCM), and water. The compatibility of the polymer
with the cosolvent system was probed using high-resolution imaging
techniques supported by molecular dynamics simulations. Solvent evaporation
and evaporation rate profiles were tracked gravimetrically to understand
the impact of the solvent composition on the evaporation process.
Short-chain alcohols, including methanol (MeOH) and ethanol (EtOH),
were found to induce drug-polymer demixing in the presence of water,
with EtOH being less sensitive to moisture than MeOH owing to its
ability to form an azeotrope with water. In contrast, water-induced
mixing was observed when higher alcohols, including <i>n-</i>propanol (PrOH) and <i>n-</i>butanol (BuOH), were used
as a cosolvent, due to the improved solubility of HPMC in the higher
alcohols in the presence of water. Isopropanol (IPA) produced phase
separated ASDs under wet and dry conditions with an increase in miscibility
with faster evaporation rates in the presence of water. This solvent-triggered
phase behavior highlights the importance of conducting a thorough
screening of various solvents prior to the preparation of ASDs via
solvent evaporation approaches such as spray drying
Mechanistic Design of Chemically Diverse Polymers with Applications in Oral Drug Delivery
Polymers
play a key role in stabilizing amorphous drug formulations,
a recent strategy employed to improve solubility and bioavailability
of drugs delivered orally. However, the molecular mechanism of stabilization
is unclear, therefore, the rational design of new crystallization-inhibiting
excipients remains a substantial challenge. This article presents
a combined experimental and computational approach to elucidate the
molecular features that improve the effectiveness of cellulose polymers
as solution crystallization inhibitors, a crucial first step toward
their rational design. Polymers with chemically diverse substituents
including carboxylic acids, esters, ethers, alcohols, amides, amines,
and sulfides were synthesized. Measurements of nucleation induction
times of the model drug, telaprevir, show that the only effective polymers
contained carboxylate groups in combination with an optimal hydrocarbon
chain length. Computational results indicate that polymer conformation
as well as solvation free energy are important determinants of effectiveness
at inhibiting crystallization and show that simulations are a promising
predictive tool in the screening of polymers. This study suggests
that polymers need to have an adequate hydrophilicity to promote solvation
in an aqueous environment, and sufficient hydrophobic regions to drive
interactions with the drug. Particularly, the right balance between
key substituent groups and lengths of hydrocarbon side chains is needed
to create effective materials
Thermodynamics and Kinetics for the Free Radical Oxygen Protein Oxidation Pathway in a Model for βâStructured Peptides
Oxidative stress plays a role in
many biological phenomena, but
involved mechanisms and individual reactions are not well understood.
Correlated electronic structure calculations with the MP2, MP4, and
CCSDÂ(T) methods detail thermodynamic and kinetic information for the
free radical oxygen protein oxidation pathway studied in a trialanine
model system. The pathway includes aerobic, anaerobic and termination
reactions. The course of the oxidation process depends on local conditions
and availability of specific reactive oxygen species (ROS). A chemical
mechanism is proposed for how oxidative stress promotes β-structure
formation in the amyloid diseases. The work can be used to aid experimentalists
as they explore individual reactions and mechanisms involving oxygen
free radicals and oxidative stress in β-structured proteins
Ď-Hydrogen Bonding in Liquid Water
We report the experimental observation and quantitation of Ď-hydrogen bond formation between liquid water and benzene using Raman multivariate curve resolution (Raman-MCR) combined with quantum and classical (cluster and liquid) calculations. Our results establish that Ď-hydrogen bonds between liquid water and benzene are weaker and more flexible (have a more positive enthalpy and entropy) than bulk water hydrogen bonds. We further establish that such bonds also form between water and other aromatics, including the amino acid phenylalanine, thus implying their common occurrence at hydrated biological interfaces