Testing and validation of the Automated Topology Builder (ATB) version 2.0: prediction of hydration free enthalpies

Koziara, Katarzyna B.; Stroet, Martin; Malde, Alpeshkumar K.; Mark, Alan E.

doi:10.1007/s10822-014-9713-7

Cited by 469 publications

(360 citation statements)

References 40 publications

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“…All simulations employed Gromos 54a7 force fields [16], calculated with the Automated Topology Builder at the University of Queensland, Brisbane, Australia [17], [18], [19], and the simple point charge (SPC) water model [20]. Micelle/substrate complexes were preformed with Packmol [21], [22], The aggregation numbers for the preformed micelles were 46 for NaU [10] and 26 for TBAU, extrapolated from [8].…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Effect of a Clathrate-Forming Counterion on Micellar Solubilization

Ogle¹,

Larrabee²

2017

Proceedings of the 2nd World Congress on New Technologies

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-Clathrate hydrates are supramolecular solids in which small, hydrophobic species are trapped inside a network of hydrogen-bonded water cages. While the best known examples are the natural gas hydrates, similar crystalline structures can also be formed from salts of tetra-n-butylammonium hydroxide (TBAOH). When TBAOH is reacted with medium to long chain carboxylic acids it produces surfactant compounds capable of forming either clathrate hydrates or micelle solutions in aqueous solution. However, little is known about how this dual nature affects the functional properties of the surfactants. Here we show a direct comparison of the solubilization of the solvatochromic dye, Nile Red (NR) by sodium 10-undecenoate (NaU) and tetrabutylammonium 10-undecenoate (TBAU). We found from the fluorescence emission spectra that the environment around NR was more polar for TBAU micellar solutions than for NaU. Molecular dynamics simulations indicated that for both systems, the NR had partial exposure to water at the surface of the micelle. The primary difference was a significant structuring of the counterions and water molecules as part of the micelle/NR complex for TBAU. Our results demonstrate an active role of role of the clathrate-forming counterion in the formation of the micelle and the solubilization of the substrate. We anticipate that the more polar environment near the surface of the micelle induced by the TBA/H 2 O structuring will enhance the solubilization power of the micelle for more polar substrates. Furthermore, we expect the more structured shell around the micelle core to enhance the isolation of the substrate from the environment, a valuable feature for applications such as targeted drug delivery.

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Section: Molecular Dynamicsmentioning

confidence: 99%

Effect of a Clathrate-Forming Counterion on Micellar Solubilization

Ogle¹,

Larrabee²

2017

Proceedings of the 2nd World Congress on New Technologies

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“…The reliability of MD simulations depends almost entirely on the force field used. While proteins are on the whole generally well described by current force fields, the description of small heteromolecular molecules that are substrates, co-factors or potential drugs are less robust and are an area of focused research in order to improve these shortcomings [143]. The improvement to the speed of the algorithms running the calculations over the past years has exploded, especially with the development and implementation of code that exploits GPU-acceleration [144,145,137].…”

Section: Discussionmentioning

confidence: 99%

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett¹

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The ability of a cell to recognise and respond to external stimuli is essential for cell survival and growth. Type-I cytokine receptors regulate many inflammatory, homeostatic, and growth and development signalling pathways. For example, the erythropoietin receptor is the main driver of red blood cell production from stem cells. All type-I cytokine receptors consist of an extracellular ligandbinding domain, a single helical transmembrane domain and an intracellular domain that associates with kinase/transcription factor signalling pathway, for example the JAK2/STAT5 pathway. Despite being extensively studied and structures of the extracellular domains of many of these receptors being known, the precise mechanism by which these receptors couple the event of ligand-binding to intracellular activation is not known. Indeed, multiple mechanisms have been proposed from experimental and crystallographic data for different receptors. For example, the activation of the growth hormone receptor is proposed to involve a relative rotation of two receptor chains, while in the case of the erythropoietin receptor the chains were suggested to separate in a scissor-like mechanism. In part, this is due to the limits of resolution achievable by experimental approaches as well as a lack of appreciation for the dynamical properties of the receptor proteins and the membrane environment.This thesis focuses on the use of fully atomistic molecular dynamics simulations to investigate the mechanism of activation for the type-I cytokine receptors. In particular MD simulations are used to probe whether conformations of the receptors observed crystallographically are representative of physiological conformations. Further to this, the quality of the X-ray crystal structures is tested by recreation of the crystal lattice in MD simulations. The effect of membrane composition is investigated by comparing the behaviour of the transmembrane domain in bulk and cholesterol-enriched raft-like bilayers. Finally, receptor dimers are examined for active and inactive conformations in raft-like bilayers containing sphingomyelin. Force field parameters for the lipid sphingomyelin that were used to build raft-like bilayers were also generated and validated. The work draws into question several of the mechanistic models proposed for the type-I cytokine receptors and demonstrates the difficulty in proposing a detailed mechanism of action based on limited sets of structural data. In particular, they highlight the limitations of the use of structural data in proposing a model when only a part of the receptor is considered. Results from the simulations also suggest that the lipid composition can influence the structure and behaviour of the receptors. Taken together the work shows the importance of considering not only the ligand-binding domain of the receptor but also the restrictions imposed by the transmembrane domain and structural influences caused by the membrane when proposing a mechanism of activation for this important class of cell surface recept...

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“…Reference Δ% *567 @ values for benzene and 11 aromatic-chloro compounds in water and hexane were calculated using an automated thermodynamic integration (TI) protocol. 56,99 The specific compounds investigated and the available experimental reference data is presented in Table 8.1. The change in the solvation energy as a function of a change in εCl and σCl (Δ% *567 >→< ) was calculated as the difference between the change in free energy in solvent and in vacuum: (37) where both ΔG *567,)& @→B and ΔG 7(2CCD @→B are calculated using Eq.…”

Section: Solvation Energy Mapsmentioning

confidence: 99%

“…All calculations were performed using the GROMOS11 simulation package 173 in conjunction with the GROMOS 54A7 force field 18 as implemented in the Automated Topology Builder (ATB) 41,99,153 .…”

Section: Simulationsmentioning

confidence: 99%

“…The initial parameters for the each of the compounds were the same as those used in Koziara et al 99 The partial charges on the atoms were obtained by applying the Merz and Kollman fitting scheme to electrostatic potential surfaces calculated at the B3LYP/6-31G* level of theory in conjunction with the PCM implicit solvation model representing water. 148 The starting structures were taken from the QM optimized geometries generated by the ATB.…”

Section: Simulationsmentioning

confidence: 99%

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Improving the accuracy of molecular dynamics simulations: parameterisation of interaction potentials for small molecules

Stroet¹

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The ability to accurately describe molecular systems with classical molecular dynamics (MD) is critically dependent on an understanding of the sources of error in the design, evaluation and analysis of the underlying model. One significant source of error is in the degree to which the equations and parameters used to represent atomic interaction can reproduce the experimental properties relevant to a particular application. While highly optimised and well-validated interaction parameters are available for common biomolecules (amino acids, sugars, lipids etc.), this is not the case for heterogeneous small molecules such as co-factors, substrates and drugs. The enormity of the chemical space covered by small molecules necessitates the development of automated approaches to parameterising and validating interaction parameters. Several tools are available that can be used to generate interaction parameters for small molecules compatible with a particular existing (bio)molecular force field. Despite their popularity, many are poorly validated, while some have been shown to be inappropriate for many applications. In other cases, validation studies have demonstrated reasonable performance, however, they also suggest significant improvements can be made. One such tool is the Automated Topology Builder (ATB, http://atb.uq.edu.au/) which provides interaction parameters for small molecules compatible with the GROMOS biomolecular force field.As part of this work, a fully automated protocol for the calculation of solvation energy by thermodynamic integration has been developed and applied to the large-scale validation of the ATB against experimental solvation data in water and hexane. It is shown that the largest errors are due to the Lennard-Jones parameters used for functional groups not present in common biomolecules. Other sources of error included the atomic charges assigned by the ATB for the united atom carbons and incompatibilities between GROMOS Lennard-Jones parameters and the ATB charge model. Significant sources of error were also identified in the evaluation of MD models, both for the calculation of solvation energy as well as for MD simulations of lipid membranes. In particular, the use of multiple-time-step algorithms as a time-saving technique. For the calculation of solvation energy by TI, the twin-range cutoff scheme-commonly used in simulations with the GROMOS force field-was found to introduce a systematic error of about 1 kJ/mol. While for lipid systems, various III changes made to the integration algorithm of the GROMACS simulation code were found to significantly alter the properties of lipid membranes when simulated with identical force fields.Finally, a method for parameterising transferrable interaction potentials with respect to a wide range of target properties 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.The consideration of surfaces in parameter space...

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Testing and validation of the Automated Topology Builder (ATB) version 2.0: prediction of hydration free enthalpies

Cited by 469 publications

References 40 publications

Effect of a Clathrate-Forming Counterion on Micellar Solubilization

Effect of a Clathrate-Forming Counterion on Micellar Solubilization

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Improving the accuracy of molecular dynamics simulations: parameterisation of interaction potentials for small molecules

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