11 research outputs found
ff14ipq: A Self-Consistent Force Field for Condensed-Phase Simulations of Proteins
We
present the ff14ipq force field, implementing the previously
published IPolQ charge set for simulations of complete proteins. Minor
modifications to the charge derivation scheme and van der Waals interactions
between polar atoms are introduced. Torsion parameters are developed
through a generational learning approach, based on gas-phase MP2/cc-pVTZ
single-point energies computed of structures optimized by the force
field itself rather than the quantum benchmark. In this manner, we
sacrifice information about the true quantum minima in order to ensure
that the force field maintains optimal agreement with the MP2/cc-pVTZ
benchmark for the ensembles it will actually produce in simulations.
A means of making the gas-phase torsion parameters compatible with
solution-phase IPolQ charges is presented. The ff14ipq model is an
alternative to ff99SB and other Amber force fields for protein simulations
in programs that accommodate pair-specific Lennard–Jones combining
rules. The force field gives strong performance on α-helical
and β-sheet oligopeptides as well as globular proteins over
microsecond time scale simulations, although it has not yet been tested
in conjunction with lipid and nucleic acid models. We show how our
choices in parameter development influence the resulting force field
and how other choices that may have appeared reasonable would actually
have led to poorer results. The tools we developed may also aid in
the development of future fixed-charge and even polarizable biomolecular
force fields
ff14ipq: A Self-Consistent Force Field for Condensed-Phase Simulations of Proteins
We
present the ff14ipq force field, implementing the previously
published IPolQ charge set for simulations of complete proteins. Minor
modifications to the charge derivation scheme and van der Waals interactions
between polar atoms are introduced. Torsion parameters are developed
through a generational learning approach, based on gas-phase MP2/cc-pVTZ
single-point energies computed of structures optimized by the force
field itself rather than the quantum benchmark. In this manner, we
sacrifice information about the true quantum minima in order to ensure
that the force field maintains optimal agreement with the MP2/cc-pVTZ
benchmark for the ensembles it will actually produce in simulations.
A means of making the gas-phase torsion parameters compatible with
solution-phase IPolQ charges is presented. The ff14ipq model is an
alternative to ff99SB and other Amber force fields for protein simulations
in programs that accommodate pair-specific Lennard–Jones combining
rules. The force field gives strong performance on α-helical
and β-sheet oligopeptides as well as globular proteins over
microsecond time scale simulations, although it has not yet been tested
in conjunction with lipid and nucleic acid models. We show how our
choices in parameter development influence the resulting force field
and how other choices that may have appeared reasonable would actually
have led to poorer results. The tools we developed may also aid in
the development of future fixed-charge and even polarizable biomolecular
force fields
Influence of Solvent on the Drug-Loading Process of Amphiphilic Nanogel Star Polymers
We
present an all-atom molecular dynamics study of the effect of
a range of organic solvents (dichloromethane, diethyl ether, toluene,
methanol, dimethyl sulfoxide, and tetrahydrofuran) on the conformations
of a nanogel star polymeric nanoparticle with solvophobic and solvophilic
structural elements. These nanoparticles are of particular interest
for drug delivery applications. As drug loading generally takes place
in an organic solvent, this work serves to provide insight into the
factors controlling the early steps of that process. Our work suggests
that nanoparticle conformational structure is highly sensitive to
the choice of solvent, providing avenues for further study as well
as predictions for both computational and experimental explorations
of the drug-loading process. Our findings suggest that when used in
the drug-loading process, dichloromethane, tetrahydrofuran, and toluene
allow for a more extensive and increased drug-loading into the interior
of nanogel star polymers of the composition studied here. In contrast,
methanol is more likely to support shallow or surface loading and,
consequently, faster drug release rates. Finally, diethyl ether should
not work in a formulation process since none of the regions of the
nanogel star polymer appear to be sufficiently solvated by it
Role of Hydrophilicity and Length of Diblock Arms for Determining Star Polymer Physical Properties
We
present a molecular simulation study of star polymers consisting
of 16 diblock copolymer arms bound to a small adamantane core by varying
both arm length and the outer hydrophilic block when attached to the
same hydrophobic block of poly-δ-valerolactone. Here we consider
two biocompatible star polymers in which the hydrophilic block is
composed of polyethylene glycol (PEG) or polymethyloxazoline (POXA)
in addition to a polycarbonate-based polymer with a pendant hydrophilic
group (PC1). We find that the different hydrophilic blocks of the
star polymers show qualitatively different trends in their interactions
with aqueous solvent, orientational time correlation functions, and
orientational correlation between pairs of monomers of their polymeric
arms in solution, in which we find that the PEG polymers are more
thermosensitive compared with the POXA and PC1 star polymers over
the physiological temperature range we have investigated
Spatial Distribution of Hydrophobic Drugs in Model Nanogel-Core Star Polymers
Star polymers with
a cross-linked nanogel core are promising carriers
of cargo for therapeutic applications due to the synthetic control
of amphiphilicity of arms and stability at infinite dilution. Three
nanogel-core star polymers were investigated to understand how the
arm-block chemical structure controls loading efficiency of a model
drug, ibuprofen, and its spatial distribution. The spatial distribution
profiles of hydrophobic core, hydrophilic corona, and encapsulated
drug were determined by small-angle neutron scattering (SANS). SANS
provides the nanometer-scale sensitivity to determine how the arm-block
chemistry enhances the sequestering of ibuprofen. Validated molecular
dynamics simulations capture the trends in drug profile and polymer
segment distribution with further details on drug orientation distribution.
This work provides a basis to study structure–function relationships
in macromolecular-based carriers of cargo and represents a path toward
validated and predictive simulation
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Effect of Hydrophobic Core Topology and Composition on the Structure and Kinetics of Star Polymers: A Molecular Dynamics Study
We
present a molecular dynamics study of the effect of core chemistry
on star polymer structural and kinetic properties. This work serves
to validate the choice of a model adamantane core used in previous
simulations to represent larger star polymeric systems in an aqueous
environment, as well as to explore how the choice of size and core
chemistry using a dendrimer or nanogel core may affect these polymeric
nanoparticle systems, particularly with respect to thermosensitivity
and solvation properties that are relevant for applications in drug
loading and delivery
Simulation and Experiments To Identify Factors Allowing Synthetic Control of Structural Features of Polymeric Nanoparticles
To develop a detailed picture of
the microscopic structure of gelcore
star polymers and to elucidate parameters of the synthetic process
that might be exploited to control this structure, simulations of
their synthesis were performed that were based on a particular synthetic
approach. A range of results was observed from gelation at high reactant
concentrations to the formation of various sizes and compositions
of star polymers. Contrary to the prevailing experimental viewpoint,
the simulations always suggest the production of a broad distribution
of star polymer sizes. However, the GPC traces computed from simulation
results are in good qualitative agreement with experiment. Topologically,
the gelcore star polymers produced by simulation are not compact but,
rather, sparse blobs loosely connected by filaments of linker when
modeled in a good solvent. This is reflected in scaling relationships
that relate polymer size (e.g., radius of gyration) and degree of
polymerization. The arm–core composition is observed to be
stoichiometric, strongly reflecting relative reactant concentrations
during the synthesis. Reactions within star polymers that result in
greater intramolecular cross-linking compete with those between star
polymers that result in the production of larger star polymers from
the joining of smaller ones. The balance in this competition can be
controlled through the overall reactant concentration to limit and
control resulting star polymer size. Therefore, the mean size, as
well as the mean number of arms, can be controlled during synthesis
by careful tuning of the overall ratio of the arm and linker reactant
concentrations and the total reactant concentration
Toward a Standard Protocol for Micelle Simulation
In
this paper, we present protocols for simulating micelles using
dissipative particle dynamics (and in principle molecular dynamics)
that we expect to be appropriate for computing micelle properties
for a wide range of surfactant molecules. The protocols address challenges
in equilibrating and sampling, specifically when kinetics can be very
different with changes in surfactant concentration, and with minor
changes in molecular size and structure, even using the same force
field parameters. We demonstrate that detection of equilibrium can
be automated and is robust, for the molecules in this study and others
we have considered. In order to quantify the degree of sampling obtained
during simulations, metrics to assess the degree of molecular exchange
among micellar material are presented, and the use of correlation
times are prescribed to assess sampling and for statistical uncertainty
estimates on the relevant simulation observables. We show that the
computational challenges facing the measurement of the critical micelle
concentration (CMC) are somewhat different for high and low CMC materials.
While a specific choice is not recommended here, we demonstrate that
various methods give values that are consistent in terms of trends,
even if not numerically equivalent
Structural transition of nanogel star polymers with pH by controlling PEGMA interactions with acid or base copolymers
<p>We use small angle X-ray scattering (SAXS) to characterise a class of star diblock polymers with a nanogel core on which the outer block arms are comprised of random copolymers of temperature sensitive PEGMA with pH sensitive basic (PDMAEMA) and acidic (PMAA) monomers. The acquired SAXS data show that many of the nanogel star polymers undergo a sharp structural transition over a narrow range of pH, but with unexpectedly large shifts in the apparent pKa with respect to that of the acidic or basic monomer unit, the linear polymer form or even an alternate star polymer with a tightly cross-linked core chemistry. We have demonstrated a distinct and quantifiable structural response for the nanogel star copolymers by altering the core or by pairing the monomers PDMAEMA–PEGMA and PMAA–PEGMA to achieve structural transitions that have typically been observed in stars through changes in arm length and number.</p> <p></p
Building a More Predictive Protein Force Field: A Systematic and Reproducible Route to AMBER-FB15
The
increasing availability of high-quality experimental data and
first-principles calculations creates opportunities for developing
more accurate empirical force fields for simulation of proteins. We
developed the AMBER-FB15 protein force field by building a high-quality
quantum chemical data set consisting of comprehensive potential energy
scans and employing the ForceBalance software package for parameter
optimization. The optimized potential surface allows for more significant
thermodynamic fluctuations away from local minima. In validation studies
where simulation results are compared to experimental measurements,
AMBER-FB15 in combination with the updated TIP3P-FB water model predicts
equilibrium properties with equivalent accuracy, and temperature dependent
properties with significantly improved accuracy, in comparison with
published models. We also discuss the effect of changing the protein
force field and water model on the simulation results