Martin Stroet

An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0

The Automated force field Topology Builder (ATB, http://compbio.biosci.uq.edu.au/atb ) is a Web-accessible server that can provide topologies and parameters for a wide range of molecules appropriate for use in molecular simulations, computational drug design, and X-ray refinement. The ATB has three primary functions: (1) to act as a repository for molecules that have been parametrized as part of the GROMOS family of force fields, (2) to act as a repository for pre-equilibrated systems for use as starting configurations in molecular dynamics simulations (solvent mixtures, lipid systems pre-equilibrated to adopt a specific phase, etc.), and (3) to generate force field descriptions of novel molecules compatible with the GROMOS family of force fields in a variety of formats (GROMOS, GROMACS, and CNS). Force field descriptions of novel molecules are derived using a multistep process in which results from quantum mechanical (QM) calculations are combined with a knowledge-based approach to ensure compatibility (as far as possible) with a specific parameter set of the GROMOS force field. The ATB has several unique features: (1) It requires that the user stipulate the protonation and tautomeric states of the molecule. (2) The symmetry of the molecule is analyzed to ensure that equivalent atoms are assigned identical parameters. (3) Charge groups are assigned automatically. (4) Where the assignment of a given parameter is ambiguous, a range of possible alternatives is provided. The ATB also provides several validation tools to assist the user to assess the degree to which the topology generated may be appropriate for a given task. In addition to detailing the steps involved in generating a force field topology compatible with a specific GROMOS parameter set (GROMOS 53A6), the challenges involved in the automatic generation of force field parameters for atomic simulations in general are discussed.

Real Cost of Speed: The Effect of a Time-Saving Multiple-Time-Stepping Algorithm on the Accuracy of Molecular Dynamics Simulations

To enhance efficiency in molecular dynamics simulations, forces that vary slowly are often evaluated less often than those that vary rapidly. We show that the multiple-time-step algorithm implemented in recent versions of GROMACS results in significant differences in the collective properties of a system under conditions where the system was previously stable. The implications of changing the simulation algorithm without assessment of potential artifacts on the parametrization and transferability of effective force fields are discussed.

The Molecular Origin of Anisotropic Emission in an Organic Light-Emitting Diode

Atomistic nonequilibrium molecular dynamics simulations have been used to model the induction of molecular orientation anisotropy within the emission layer of an organic light-emitting diode (OLED) formed by vapor deposition. Two emitter species were compared: racemic fac-tris(2-phenylpyridine)iridium(III) (Ir(ppy)3) and trans-bis(2-phenylpyridine)(acetylacetonate)iridium(III) (Ir(ppy)2(acac)). The simulations show that the molecular symmetry axes of both emitters preferentially align perpendicular to the surface during deposition. The molecular arrangement formed on deposition combined with consideration of the transition dipole moments provides insight into experimental reports that Ir(ppy)3 shows isotropic emission, while Ir(ppy)2(acac) displays improved efficiency due to an apparent preferential alignment of the transition dipole vectors parallel to the substrate. The simulations indicate that this difference is not due to differences in the extent of emitter alignment, but rather differences in the direction of the transition dipoles within the two complexes.

Optimization of Empirical Force Fields by Parameter Space Mapping: A Single-Step Perturbation Approach

A general method for parametrizing atomic interaction functions is presented. The method is based on an analysis of surfaces corresponding to the difference between calculated and target data as a function of alternative combinations of parameters (parameter space mapping). The consideration of surfaces in parameter space as opposed to local values or gradients leads to a better understanding of the relationships between the parameters being optimized and a given set of target data. This in turn enables for a range of target data from multiple molecules to be combined in a robust manner and for the optimal region of parameter space to be trivially identified. The effectiveness of the approach is illustrated by using the method to refine the chlorine 6-12 Lennard-Jones parameters against experimental solvation free enthalpies in water and hexane as well as the density and heat of vaporization of the liquid at atmospheric pressure for a set of 10 aromatic-chloro compounds simultaneously. Single-step perturbation is used to efficiently calculate solvation free enthalpies for a wide range of parameter combinations. The capacity of this approach to parametrize accurate and transferrable force fields is discussed.

Computational modelling of optical tweezers with many degrees of freedom using dynamic simulation: cylinders, nanowires, and multiple particles

Computational tasks such as the calculation and characterization of the optical force acting on a sphere are relatively straightforward in a Gaussian beam trap. Resulting properties of the trap such as the trap strength, spring constants, and equilibrium position can be easily determined. More complex systems with non-spherical particles or multiple particles add many more degrees of freedom to the problem. Extension of the simple methods used for single spherical particles could result in required computational time of months or years. Thus, alternative methods must be used. One powerful tool is to use dynamic simulation: model the dynamics and motion of a particle or particles within the trap. We demonstrate the use of dynamic simulation for non-spherical particles and multi-particle systems. Using a hybrid discrete dipole approximation (DDA) and T-matrix method, we find plausible equilibrium positions and orientations of cylinders of varying size and aspect ratio. Orientation landscapes revealing different regimes of behaviour for micro-cylinders and nanowires with different refractive indices trapped with beams of differing polarization are also presented. This investigation provides a solid background in both the function and properties of micro-cylinders and nanowires trapped in optical tweezers. This method can also be applied to particles with other shapes. We also investigate multiple-particle trapping, which is quite different from single particle systems, as they can include effects such as optical binding. We show that equilibrium positions, and the strength of interactions between particles can be found in systems of two and more particles.

Predicting the Prevalence of Alternative Warfarin Tautomers in Solution

Warfarin, a widely used oral anticoagulant, is prescribed as a racemic mixture. Each enantiomer of neutral Warfarin can exist in 20 possible tautomeric states leading to complex pharmacokinetics and uncertainty as to the relevant species under different conditions. Here, the ability of alternative computational approaches to predict the preferred tautomeric form(s) of neutral Warfarin in different solvents is examined. It is shown that varying the method used to estimate the heat of formation in vacuum (direct or via homodesmic reactions), whether entropic corrections were included, and the method used to estimate the free enthalpy of solvation (i.e., PCM, COSMO, or SMD implicit models or explicit solvent) lead to large differences in the predicted rank and relative populations of the tautomers. In this case, only a combination of the enthalpy of formation using homodesmic reactions and explicit solvent to estimate the free enthalpy of solvation yielded results compatible with the available experimental data. The work also suggests that a small but significant subset of the possible Warfarin tautomers are likely to be physiologically relevant.

Automated Topology Builder Version 3.0: Prediction of Solvation Free Enthalpies in Water and Hexane

The ability of atomic interaction parameters generated using the Automated Topology Builder and Repository version 3.0 (ATB3.0) to predict experimental hydration free enthalpies (Δ Gwater) and solvation free enthalpies in the apolar solvent hexane (Δ Ghexane) is presented. For a validation set of 685 molecules the average unsigned error (AUE) between Δ Gwater values calculated using the ATB3.0 and experiment is 3.8 kJ·mol-1. The slope of the line of best fit is 1.00, the intercept -1.0 kJ·mol-1, and the R2 0.90. For the more restricted set of 239 molecules used to validate OPLS3 ( J. Chem. Theory Comput. 2016 , 12 , 281 - 296 , DOI: 10.1021/acs.jctc.5b00864 ) the AUE using the ATB3.0 is just 2.7 kJ·mol-1 and the R2 0.93. A roadmap for further improvement of the ATB parameters is presented together with a discussion of the challenges of validating force fields against the available experimental data.