GROMACS molecule & liquid database van der Spoel, David; van Maaren, Paul J; Caleman, Carl
Bioinformatics (Oxford, England),
03/2012, Letnik:
28, Številka:
5
Journal Article
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MOTIVATION: The molecular dynamics simulation package GROMACS is a widely used tool used in a broad range of different applications within physics, chemistry and biology. It is freely available, user ...friendly and extremely efficient. The GROMACS software is force field agnostic, and compatible with many molecular dynamics force fields; coarse-grained, unified atom, all atom as well as polarizable models based on the charge on a spring concept. To validate simulations, it is necessary to compare results from the simulations to experimental data. To ease the process of setting up topologies and structures for simulations, as well as providing pre-calculated physical properties along with experimental values for the same we provide a web-based database, containing 145 organic molecules at present. RESULTS: Liquid properties of 145 organic molecules have been simulated using two different force fields, OPLS all atom and Generalized Amber Force Field. So far, eight properties have been calculated (the density, enthalpy of vaporization, surface tension, heat capacity at constant volume and pressure, isothermal compressibility, volumetric expansion coefficient and the static dielectric constant). The results, together with experimental values are available through the database, along with liquid structures and topologies for the 145 molecules, in the two force fields. AVAILABILITY: The database is freely available under http://virtualchemistry.org. CONTACT: spoel@xray.bmc.uu.se; carl.caleman@cfel.de
The chemical composition of small organic molecules is often very similar to amino acid side chains or the bases in nucleic acids, and hence there is no a priori reason why a molecular mechanics ...force field could not describe both organic liquids and biomolecules with a single parameter set. Here, we devise a benchmark for force fields in order to test the ability of existing force fields to reproduce some key properties of organic liquids, namely, the density, enthalpy of vaporization, the surface tension, the heat capacity at constant volume and pressure, the isothermal compressibility, the volumetric expansion coefficient, and the static dielectric constant. Well over 1200 experimental measurements were used for comparison to the simulations of 146 organic liquids. Novel polynomial interpolations of the dielectric constant (32 molecules), heat capacity at constant pressure (three molecules), and the isothermal compressibility (53 molecules) as a function of the temperature have been made, based on experimental data, in order to be able to compare simulation results to them. To compute the heat capacities, we applied the two phase thermodynamics method (Lin et al. J. Chem. Phys. 2003, 119, 11792), which allows one to compute thermodynamic properties on the basis of the density of states as derived from the velocity autocorrelation function. The method is implemented in a new utility within the GROMACS molecular simulation package, named g_dos, and a detailed exposé of the underlying equations is presented. The purpose of this work is to establish the state of the art of two popular force fields, OPLS/AA (all-atom optimized potential for liquid simulation) and GAFF (generalized Amber force field), to find common bottlenecks, i.e., particularly difficult molecules, and to serve as a reference point for future force field development. To make for a fair playing field, all molecules were evaluated with the same parameter settings, such as thermostats and barostats, treatment of electrostatic interactions, and system size (1000 molecules). The densities and enthalpy of vaporization from an independent data set based on simulations using the CHARMM General Force Field (CGenFF) presented by Vanommeslaeghe et al. (J. Comput. Chem. 2010, 31, 671) are included for comparison. We find that, overall, the OPLS/AA force field performs somewhat better than GAFF, but there are significant issues with reproduction of the surface tension and dielectric constants for both force fields.
The thermodynamics of hydrogen bond breaking and formation was studied in solutions of alcohol (methanol, ethanol, 1-propanol) molecules. An extensive series of over 400 molecular dynamics ...simulations with an aggregate length of over 900 ns was analyzed using an analysis technique in which hydrogen bond (HB) breaking is interpreted as an Eyring process, for which the Gibbs energy of activation ΔG⧧ can be determined from the HB lifetime. By performing simulations at different temperatures, we were able to determine the enthalpy of activation ΔH ⧧ and the entropy of activation TΔS ⧧ for this process from the Van't Hoff relation. The equilibrium thermodynamics was determined separately, based on the number of donor hydrogens that are involved in hydrogen bonds. Results (ΔH) are compared to experimental data from Raman spectroscopy and found to be in good agreement for pure water and methanol. The ΔG as well as the ΔG ⧧ are smooth functions of the composition of the mixtures. The main result of the calculations is that ΔG is essentially independent of the environment (around 5 kJ/mol), suggesting that buried hydrogen bonds (e.g., in proteins) do not contribute significantly to protein stability. Enthalpically HB formation is a downhill process in all substances; however, for the alcohols there is an entropic barrier of 6−7 kJ/mol, at 298.15 K, which cannot be detected in pure water.
Our study aimed to provide a comprehensive overview of trends in incidence, survival, mortality and treatment of first primary invasive breast cancer (BC), according to age, stage and receptor ...subtype in the Netherlands between 1989 and 2017. Data from all women diagnosed with first primary stage I to IV BC (N = 320 249) were obtained from the Netherlands Cancer Registry. BC mortality and general population data were retrieved from Statistics Netherlands. Age‐standardised incidence and mortality rates were calculated with annual percentage change (APC) and average annual percentage change (AAPC) statistics. The relative survival (RS) was used as estimator for disease‐specific survival. The BC incidence for all BC patients combined significantly increased until 2013 from 126 to 158 per 100 000 person‐years, after which a declining trend was observed. Surgery became less extensive, but (neo‐)adjuvant systemic treatments and their combinations were given more frequently. The RS improved for all age groups and for most stages and receptor subtypes, but remained stable for all subtypes since 2012 to 2013 and since 2000 to 2009 for Stage IV BC at 15 years of follow‐up. Overall, the 5‐ and 10‐year RS increased from 76.8% (95% confidence interval CI: 76.1, 77.4) and 55.9% (95% CI: 54.7, 57.1) in 1989 to 1999 to 91.0% (95% CI: 90.5, 91.5) and 82.9% (95% CI: 82.2, 83.5), respectively, in 2010 to 2016. BC mortality improved regardless of age and overall decreased from 57 to 35 per 100 000 person‐years between 1989 and 2017. In conclusion, the BC incidence in the Netherlands has steadily increased since 1989, but the latest trends show promising declines. Survival improved markedly for most patients and the mortality decreased regardless of age.
What's new?
Studies that simultaneously capture incidence, survival, and mortality trends in breast cancer are scarce, and receptor subtype‐specific trends have remained largely unexplored. This study provides an up‐to‐date and comprehensive overview of first primary invasive breast cancer trends in the Netherlands in 1989 to 2017. Breast cancer incidence increased for all breast cancer patients combined until 2013, but the latest trends show a promising decline. Treatment strategies became more complex. Relative survival improved for all age groups and for most stages and receptor subtypes, and mortality decreased overall. The results may be useful in supporting healthcare management and informing current clinical practice.
Water is a demanding partner. It strongly attracts ions, yet some halide anions--chloride, bromide, and iodide--are expelled to the air/water interface. This has important implications for chemistry ...in the atmosphere, including the ozone cycle. We present a quantitative analysis of the energetics of ion solvation based on molecular simulations of all stable alkali and halide ions in water droplets. The potentials of mean force for Clâ», Brâ», and Iâ» have shallow minima near the surface. We demonstrate that these minima derive from more favorable water-water interaction energy when the ions are partially desolvated. Alkali cations are on the inside because of the favorable ion-water energy, whereas Fâ» is driven inside by entropy. Models attempting to explain the surface preference based on one or more ion properties such as polarizability or size are shown to lead to qualitative and quantitative errors, prompting a paradigm shift in chemistry away from such simplifications.
A recent paper (Yonetani, Chem. Phys. Lett. 2005, 406, 49−53) shows that in computer simulations of TIP3P water (Jorgensen et al. J. Chem. Phys. 1983, 79, 926−935) a strange layer formation can occur ...when a long cutoff is used. This result is counterintuitive because, in principle, increasing the cutoff should give more accurate results. Here we test this finding for different water models and try to explain why layer formation occurs. In doing so we find that under certain conditions, layer formation coincides with a sharp density increase to 1050 g/L, while simultaneously a pressure of 600 bar develops and water diffusion becomes anisotropic. This leads us to conclude that a group-based cutoff (of at least 1.4 nm) stabilizes an anomalous phase with most water models. In some cases the ordering is strengthened further by periodicity in the simulation cell, but periodicity effects can even be observed with a short cutoff (0.9 nm) and a relatively large box of 4 nm. Water models that have a relatively large quadrupole moment, more in accord with the experimental gas-phase values, in particular TIP4P (Jorgensen et al. J. Chem. Phys. 1983, 79, 926−935), are much less affected by the problem, because the dipole−dipole interaction is quenched at long distance. A comparison of different cutoff treatments, namely truncation, reaction field, particle mesh Ewald (PME), and switch and shift functions, for the simulation of water shows that only PME and shift functions yield realistic dipole−dipole interactions at long distance. The impact for biomolecular simulations is discussed.
In order to increase the accuracy of classical computer simulations, existing methodologies may need to be adapted. Hitherto, most force fields employ a truncated potential function to model van der ...Waals interactions, sometimes augmented with an analytical correction. Although such corrections are accurate for homogeneous systems with a long cutoff, they should not be used in inherently inhomogeneous systems such as biomolecular and interface systems. For such cases, a variant of the particle mesh Ewald algorithm (Lennard-Jones PME) was already proposed 20 years ago (Essmann et al. J. Chem. Phys. 1995, 103, 8577–8593), but it was implemented only recently (Wennberg et al. J. Chem. Theory Comput. 2013, 9, 3527–3537) in a major simulation code (GROMACS). The availability of this method allows surface tensions of liquids as well as bulk properties to be established, such as density and enthalpy of vaporization, without approximations due to truncation. Here, we report on simulations of ≈150 liquids (taken from a force field benchmark: Caleman et al. J. Chem. Theory Comput. 2012, 8, 61–74) using three different force fields and compare simulations with and without explicit long-range van der Waals interactions. We find that the density and enthalpy of vaporization increase for most liquids using the generalized Amber force field (GAFF, Wang et al. J. Comput. Chem. 2004, 25, 1157–1174) and the Charmm generalized force field (CGenFF, Vanommeslaeghe et al. J. Comput. Chem. 2010, 31, 671–690) but less so for OPLS/AA (Jorgensen and Tirado-Rives, Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 6665–6670), which was parametrized with an analytical correction to the van der Waals potential. The surface tension increases by ≈10–2 N/m for all force fields. These results suggest that van der Waals attractions in force fields are too strong, in particular for the GAFF and CGenFF. In addition to the simulation results, we introduce a new version of a web server, http://virtualchemistry.org, aimed at facilitating sharing and reuse of input files for molecular simulations.
The systems of noble gases are particularly instructive for molecular modeling due to the elemental nature of their interactions. They do not normally form bonds nor possess a (permanent) dipole ...moment, and the only forces determining their bonding/clustering stems from van der Waals forcesdispersion and Pauli repulsion, which can be modeled by empirical potential functions. Combination rules, that is, formulas to derive parameters for pair potentials of heterodimers from parameters of corresponding homodimers, have been studied at length for the Lennard-Jones 12-6 potentials but not in great detail for other, more accurate, potentials. In this work, we examine the usefulness of nine empirical potentials in their ability to reproduce quantum mechanical (QM) benchmark dissociation curves of noble gas dimers (He, Ne, Ar, Kr, and Xe homo- and heterodimers), and we systematically study the efficacy of different permutations of combination relations for each parameter of the potentials. Our QM benchmark comprises dissociation curves computed by several different coupled cluster implementations as well as symmetry-adapted perturbation theory. The two-parameter Lennard-Jones potentials were decisively outperformed by more elaborate potentials that sport a 25–30 times lower root-mean-square error (RMSE) when fitted to QM dissociation curves. Very good fits to the QM dissociation curves can be achieved with relatively inexpensive four- or even three-parameter potentials, for instance, the damped 14-7 potential (Halgren, J. Am. Chem. Soc. 1992, 114, 7827–7843), a four-parameter Buckingham potential (Werhahn et al., Chem. Phys. Lett. 2015, 619, 133–138), or the three-parameter Morse potential (Morse, Phys. Rev. 1929, 34, 57–64). Potentials for heterodimers that are generated from combination rules have an RMSE that is up to 20 times higher than potentials that are directly fitted to the QM dissociation curves. This means that the RMSE, in particular, for light atoms, is comparable in magnitude to the well-depth of the potential. Based on a systematic permutation of combination rules, we present one or more combination rules for each potential tested that yield a relatively low RMSE. Two new combination rules are introduced that perform well, one for the van der Waals radius σ ij as ( 1 2 ( σ i 3 + σ j 3 ) ) 1 / 3 and one for the well-depth ϵ ij as ( 1 2 ( ϵ i − 2 + ϵ j − 2 ) ) − 1 / 2 . The QM data and the fitted potentials were evaluated in the gas phase against experimental second virial coefficients for homo- and heterodimers, the latter of which allowed evaluation of the combination rules. The fitted models were used to perform condensed phase molecular dynamics simulations to verify the melting points, liquid densities at the melting point, and the enthalpies of vaporization produced by the models for pure substances. Subtle differences in the benchmark potentials, in particular, the well-depth, due to the level of theory used were found here to have a profound effect on the macroscopic properties of noble gases: second virial coefficients or the bulk properties in simulations. By explicitly including three-body dispersion in molecular simulations employing the best pair potential, we were able to obtain accurate melting points as well as satisfactory densities and enthalpies of vaporization.
Background
Despite the potential for residual lymph node metastases after a negative or positive sentinel lymph node biopsy (SLNB), breast cancer patients rarely experience regional recurrences ...(RRs). This study aimed to quantify the effects of nonsurgical treatments on RR incidence among SLNB-negative (SLNB N0) breast cancer patients.
Methods
All primary SLNB N0-staged breast cancer patients with a diagnosis between 2005 and 2008 and 5-year follow-up data on recurrences were selected from the Netherlands Cancer Registry. The cumulative incidence function (CIF) for RR was calculated as the first event at 5 years, taking into account any other first-event (local or distant recurrence, contralateral breast cancer, or death) as competing risk. Cox regression analysis was used to model the cause-specific hazard of RR developing as the first event to quantify the effect of adjuvant systemic therapy and whole-breast radiotherapy (RT) on RR incidence at 5 years.
Results
The study included 13,512 patients. Of these patients, 162 experienced an RR. The CIF of RR at 5 years was 1.3% (95% confidence interval CI, 1.1–1.5%), whereas the CIFs for death and other events were 4.4% and 9.5%, respectively. Cox regression analysis showed hazard ratios (HRs) of 0.46 (95% CI 0.33–0.64), 0.31 (95% CI 0.18–0.55), and 0.40 (95% CI 0.24–0.67) respectively for patients treated by RT as a routine part of breast-conserving therapy (BCT), chemotherapy, and hormonal therapy.
Conclusion
RT as routine part of BCT, chemotherapy, and hormonal therapy independently exerted a mitigating effect on the risk for the development of RR. The three methods at least halved the risk.
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