We propose to develop several essential components that would allow comprehensive modeling of glycoproteins in ICM: a carbohydrate extension of the ECEPP05 force-field, a library of common glycosylating moieties, tools for glycan construction on protein structures, and simulations of their stochastic dynamics and docking to glycan-binding proteins. Together these components will comprise the Glycosylation Modeling System. Carbohydrate moieties on the proteins (glycans) play an essential role in a range of physiological processes, including viral evasion from the immune system, blood anticoagulation, the progression of cancer, cell-cell recognition, and the correct folding and processing of proteins. Understanding of their function on the level of three-dimensional structure has been lagging behind that of the regular polypeptides. Flexibility, disorder and heterogeneity of glycans make experimental structure determination difficult. Molecular mechanics techniques increasingly allow in-silico simulation of essential biological processes at the atomic level. Molsoft's ICM (Internal Coordinate Mechanics) software platform is a particularly efficient modeling tool because of its use of internal variables, rather than traditional Cartesian coordinates, in the description of the molecular structure. This proposed development will allow to apply this approach to modeling of carbohydrates. Equipping structural biologists with the Glycoprotein Modeling System in ICM will help bring molecular simulations and structure predictions for glycans to the next level of accuracy. Successful structure modeling will ultimately help improve our understanding of molecular mechanisms underlying disease and help to accelerate structure-based drug discovery efforts.
Carbohydrate moieties on the proteins (glycans) play an essential role in a range of physiological processes, including viral evasion from the immune system, blood anticoagulation, the progression of cancer, cell-cell recognition, and the correct folding and processing of proteins. Equipping structural biologists with the Glycoprotein Modeling System in ICM will help bring molecular simulations and structure predictions for glycans to the next level of accuracy. Successful structure modeling will ultimately help improve our understanding of molecular mechanisms underlying disease and help accelerate structure-based drug discovery efforts.
| Gastegger, Michael; Marquetand, Philipp (2015) High-Dimensional Neural Network Potentials for Organic Reactions and an Improved Training Algorithm. J Chem Theory Comput 11:2187-98 |
