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Residue-centric modeling and design of saccharide and glycoconjugate structures.

ABSTRACT: The RosettaCarbohydrate framework is a new tool for modeling a wide variety of saccharide and glycoconjugate structures. This report describes the development of the framework and highlights its applications. The framework integrates with established protocols within the Rosetta modeling and design suite, and it handles the vast complexity and variety of carbohydrate molecules, including branching and sugar modifications. To address challenges of sampling and scoring, RosettaCarbohydrate can sample glycosidic bonds, side-chain conformations, and ring forms, and it utilizes a glycan-specific term within its scoring function. Rosetta can work with standard PDB, GLYCAM, and GlycoWorkbench (.gws) file formats. Saccharide residue-specific chemical information is stored internally, permitting glycoengineering and design. Carbohydrate-specific applications described herein include virtual glycosylation, loop-modeling of carbohydrates, and docking of glyco-ligands to antibodies. Benchmarking data are presented and compared to other studies, demonstrating Rosetta's ability to predict glyco-ligand binding. The framework expands the tools available to glycoscientists and engineers. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Labonte JW

PROVIDER: S-EPMC5182120 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Residue-centric modeling and design of saccharide and glycoconjugate structures.

Labonte Jason W JW Adolf-Bryfogle Jared J Schief William R WR Gray Jeffrey J JJ

Journal of computational chemistry 20161130 5

The RosettaCarbohydrate framework is a new tool for modeling a wide variety of saccharide and glycoconjugate structures. This report describes the development of the framework and highlights its applications. The framework integrates with established protocols within the Rosetta modeling and design suite, and it handles the vast complexity and variety of carbohydrate molecules, including branching and sugar modifications. To address challenges of sampling and scoring, RosettaCarbohydrate can sam ...[more]

PMID: 27900782

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Project description:Proteins are typically represented by discrete atomic coordinates providing an accessible framework to describe different conformations. However, in some fields proteins are more accurately represented as near-continuous surfaces, as these are imprinted with geometric (shape) and chemical (electrostatics) features of the underlying protein structure. Protein surfaces are dependent on their chemical composition and, ultimately determine protein function, acting as the interface that engages in interactions with other molecules. In the past, such representations were utilized to compare protein structures on global and local scales and have shed light on functional properties of proteins. Here we describe RosettaSurf, a surface-centric computational design protocol, that focuses on the molecular surface shape and electrostatic properties as means for protein engineering, offering a unique approach for the design of proteins and their functions. The RosettaSurf protocol combines the explicit optimization of molecular surface features with a global scoring function during the sequence design process, diverging from the typical design approaches that rely solely on an energy scoring function. With this computational approach, we attempt to address a fundamental problem in protein design related to the design of functional sites in proteins, even when structurally similar templates are absent in the characterized structural repertoire. Surface-centric design exploits the premise that molecular surfaces are, to a certain extent, independent of the underlying sequence and backbone configuration, meaning that different sequences in different proteins may present similar surfaces. We benchmarked RosettaSurf on various sequence recovery datasets and showcased its design capabilities by generating epitope mimics that were biochemically validated. Overall, our results indicate that the explicit optimization of surface features may lead to new routes for the design of functional proteins.

Dataset Information

Residue-centric modeling and design of saccharide and glycoconjugate structures.

Publications

Residue-centric modeling and design of saccharide and glycoconjugate structures.

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