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Molecular dynamics simulations of glycoproteins using CHARMM.

ABSTRACT: Molecular dynamics simulations are an effective tool to study the structure, dynamics, and thermodynamics of carbohydrates and proteins. However, the simulations of heterogeneous glycoprotein systems have been limited due to the lack of appropriate molecular force field parameters describing the linkage between the carbohydrate and the protein regions as well as the tools to prepare these systems for modeling studies. In this work we outline the recent developments in the CHARMM carbohydrate force field to treat glycoproteins and describe in detail the step-by-step procedures involved in building glycoprotein geometries using CHARMM-GUI Glycan Reader.

SUBMITTER: Mallajosyula SS

PROVIDER: S-EPMC4537648 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Molecular dynamics simulations of glycoproteins using CHARMM.

Mallajosyula Sairam S SS Jo Sunhwan S Im Wonpil W MacKerell Alexander D AD

Methods in molecular biology (Clifton, N.J.) 20150101

Molecular dynamics simulations are an effective tool to study the structure, dynamics, and thermodynamics of carbohydrates and proteins. However, the simulations of heterogeneous glycoprotein systems have been limited due to the lack of appropriate molecular force field parameters describing the linkage between the carbohydrate and the protein regions as well as the tools to prepare these systems for modeling studies. In this work we outline the recent developments in the CHARMM carbohydrate for ...[more]

PMID: 25753723

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Project description:All-atom molecular dynamics simulations with stratified alchemical free energy calculations were used to predict the octanol-water partition coefficient [Formula: see text] of eleven small molecules as part of the SAMPL6-[Formula: see text] blind prediction challenge using four different force field parametrizations: standard OPLS-AA with transferable charges, OPLS-AA with non-transferable CM1A charges, AMBER/GAFF, and CHARMM/CGenFF. Octanol parameters for OPLS-AA, GAFF and CHARMM were validated by comparing the density as a function of temperature, the chemical potential, and the hydration free energy to experimental values. The partition coefficients were calculated from the solvation free energy for the compounds in water and pure ("dry") octanol or "wet" octanol with 27 mol% water dissolved. Absolute solvation free energies were computed by thermodynamic integration (TI) and the multistate Bennett acceptance ratio with uncorrelated samples from data generated by an established protocol using 5-ns windowed alchemical free energy perturbation (FEP) calculations with the Gromacs molecular dynamics package. Equilibration of sets of FEP simulations was quantified by a new measure of convergence based on the analysis of forward and time-reversed trajectories. The accuracy of the [Formula: see text] predictions was assessed by descriptive statistical measures such as the root mean square error (RMSE) of the data set compared to the experimental values. Discarding the first 1 ns of each 5-ns window as an equilibration phase had a large effect on the GAFF data, where it improved the RMSE by up to 0.8 log units, while the effect for other data sets was smaller or marginally worsened the agreement. Overall, CGenFF gave the best prediction with RMSE 1.2 log units, although for only eight molecules because the current CGenFF workflow for Gromacs does not generate files for certain halogen-containing compounds. Over all eleven compounds, GAFF gave an RMSE of 1.5. The effect of using a mixed water/octanol solvent slightly decreased the accuracy for CGenFF and GAFF and slightly increased it for OPLS-AA. The GAFF and OPLS-AA results displayed a systematic error where molecules were too hydrophobic whereas CGenFF appeared to be more balanced, at least on this small data set.

Dataset Information

Molecular dynamics simulations of glycoproteins using CHARMM.

Publications

Molecular dynamics simulations of glycoproteins using CHARMM.

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