34 research outputs found
Benchmarking Electronic Structure Methods for Accurate Fixed-Charge Electrostatic Models
The accuracy of classical molecular mechanics (MM) force fields used for condensed phase molecular simulations depends strongly on the accuracy of modeling nonbonded interactions between atoms, such as electrostatic interactions. Some popular fixed-charge MM force fields use partial atomic charges derived from gas phase electronic structure calculations using the Hartree-Fock method with the relatively small 6-31G* basis set (HF/6-31G*). It is generally believed that HF/6-31G* generates fortuitously overpolarized electron distributions, as would be expected in the higher dielectric environment of the condensed phase. Using a benchmark set of 47 molecules we show that HF/6-31G* overpolarizes molecules by just under 10% on average with respect to experimental gas phase dipole moments. The overpolarization of this method/basis set combination varies significantly though and, in some cases, even leads to molecular dipole moments that are lower than experimental gas phase measurements. We further demonstrate that using computationally inexpensive density functional theory (DFT) methods, together with appropriate augmented basis sets and a continuum solvent model, can yield molecular dipole moments that are both more strongly and more uniformly overpolarized. These data suggest that these methods – or ones similar to them – should be adopted for the derivation of accurate partial atomic charges for next-generation MM force fields.</p
Probing the Structural and Binding Mechanism Heterogeneity of Molecularly Imprinted Polymers
We devised a strategy, using a de
novo building approach, to construct
model molecularly imprinted polymers (MIPs) and assess their ability
at binding various target molecules. While our models successfully
reproduce the gross experimental selectivities for two xanthines,
our atomistic models reveal in detail the considerable heterogeneity
of the structure and binding mechanisms of different imprints within
such a material. We also demonstrate how nonimprinted regions of a
MIP are also responsible for much of binding of target molecules.
High levels of cross-linking are shown to produce less specific imprints
Data-driven analysis of the number of Lennard-Jones types needed in a force field
We optimized force fields with smaller and
larger sets of chemically motivated Lennard-Jones types against the
experimental properties of organic liquids. Surprisingly, we obtained results as good as or
better than those from much more complex typing schemes from exceedingly
simple sets of LJ types; e.g. a model with only two types of hydrogen and
only one type apiece for carbon, nitrogen and oxygen.The results justify sharply limiting the number of
parameters to be optimized in future force field development work, thus
reducing the risks of overfitting and the difficulties of reaching a global
optimum in the multidimensional parameter space. They thus increase our chances of arriving at well-optimized
force fields that will improve predictive accuracy, with applications in
biomolecular modeling and computer-aided drug design. The results also prove the feasibility and value of a
rigorous, data-driven approach to advancing the science of force field
development.</p
A fast, convenient, polarizable electrostatic model for molecular dynamics
We present an efficient polarizable electrostatic model, utilizing typed, atom-centered, polarizabilities and the fast direct approximation, designed for efficient use in molecular dynamics (MD) simulations. The model provides two convenient approaches to assigning partial charges in the context of the atomic polarizabilities. One is a generalization of RESP, called RESP-dPol, and the other, AM1-BCC-dPol, is an adaptation of the widely used AM1-BCC method. Both are designed to accurately replicate gas-phase QM electrostatic potentials. Benchmarks of this polarizable electrostatic model against gas-phase dipole moments, molecular polarizabilities, bulk liquid densities, and static dielectric constants of organic liquids, show good agreement with the reference values. Of note, the model yields markedly more accurate dielectric constants of organic liquids, relative to a matched non-polarizable force field. MD simulations with this method, which is currently parameterized for molecules containing elements C, N, O, and H, run about only 3.6-fold slower than fixed charge force fields, while simulations with the self-consistent mutual polarization average 4.5-fold slower. Our results suggest that RESP-dPol and AM1-BCC-dPol afford improved accuracy, relative to fixed charge force fields, and are good starting points for developing general, affordable, and transferable polarizable force fields. The software implementing these approaches has been designed to utilize the force field fitting frameworks developed and maintained by Open Force Field Initiative, setting the stage for further exploration of this approach to polarizable force field development
Data-driven analysis of the number of Lennard–Jones types needed in a force field
Force fields used in molecular simulations contain numerical parameters, such as Lennard-Jones (LJ) parameters, which are assigned to the atoms in a molecule based on a classification of their chemical environments. The number of classes, or types, should be no more than needed to maximize agreement with experiment, as parsimony avoids overfitting and simplifies parameter optimization. However, types have historically been crafted based largely on chemical intuition, so current force fields may contain more types than needed. In this study, we seek the minimum number of LJ parameter types needed to represent key properties of organic liquids. We find that highly competitive force field accuracy is obtained with minimalist sets of LJ types; e.g. two H types and one type apiece for C, O, and N atoms. We also find that the fitness surface has multiple minima, which can lead to local trapping of the optimizer
Quantum Chemical Microsolvation by Automated Water Placement
We developed a quantitative approach to quantum chemical microsolvation. Key in our methodology is the automatic placement of individual solvent molecules based on the free energy solvation thermodynamics derived from molecular dynamics (MD) simulations and grid inhomogeneous solvation theory (GIST). This protocol enabled us to rigorously define the number, position, and orientation of individual solvent molecules and to determine their interaction with the solute based on physical quantities. The generated solute–solvent clusters served as an input for subsequent quantum chemical investigations. We showcased the applicability, scope, and limitations of this computational approach for a number of small molecules, including urea, 2-aminobenzothiazole, (+)-syn-benzotriborneol, benzoic acid, and helicene. Our results show excellent agreement with the available ab initio molecular dynamics data and experimental results.ISSN:1420-304
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A Fast, Convenient, Polarizable Electrostatic Model for Molecular Dynamics
We present an efficient polarizable electrostatic model, utilizing typed, atom-centered polarizabilities and the fast direct approximation, designed for efficient use in molecular dynamics (MD) simulations. The model provides two convenient approaches for assigning partial charges in the context of atomic polarizabilities. One is a generalization of RESP, called RESP-dPol, and the other, AM1-BCC-dPol, is an adaptation of the widely used AM1-BCC method. Both are designed to accurately replicate gas-phase quantum mechanical electrostatic potentials. Benchmarks of this polarizable electrostatic model against gas-phase dipole moments, molecular polarizabilities, bulk liquid densities, and static dielectric constants of organic liquids show good agreement with the reference values. Of note, the model yields markedly more accurate dielectric constants of organic liquids, relative to a matched nonpolarizable force field. MD simulations with this method, which is currently parametrized for molecules containing elements C, N, O, and H, run only about 3.6-fold slower than fixed charge force fields, while simulations with the self-consistent mutual polarization average 4.5-fold slower. Our results suggest that RESP-dPol and AM1-BCC-dPol afford improved accuracy relative to fixed charge force fields and are good starting points for developing general, affordable, and transferable polarizable force fields. The software implementing these approaches has been designed to utilize the force field fitting frameworks developed and maintained by the Open Force Field Initiative, setting the stage for further exploration of this approach to polarizable force field development
Experimental Characterization of the Association of Nine Novel Cyclodextrin Derivatives with Two Guest Compounds
We investigate the binding of native β-cyclodextrin (β-CD) and eight novel β-CD derivatives with two different
guest compounds, using isothermal calorimetry (ITC) and 2D NOESY NMR. In all cases, the stoichiometry is 1:1
and binding is exothermic. Overall, modifications at the 3’ position of β-CD, which is at the secondary face, weaken
binding by several kJ/mol relative to native β-CD, while modifications at the 6’ position (primary face) maintain or
somewhat reduce the binding affinity. The variations in binding enthalpy are larger than the variations in binding
free energy, so entropy-enthalpy compensation is observed. Characterization of the bound conformations with
NOESY NMR shows that the polar groups of the guests may be situated at either face, depending on the host
molecule, and, in some cases, both orientations are populated. The present results were used in the SAMPL7 blinded
prediction challenge whose results are detailed in the same special issue of JCAMD