MOE™: Molecular Operating Environment

Biologics Applications

MOE has a comprehensive suite of applications for computer aided biologics design including a workflow oriented interface for streamlined visualization and analysis. Computational methods help identify and prioritize potential mutagenesis experiments for property modulation such as solubility, affinity and stability.

MOE - surface patches Visualize protein:protein interface regions for non-bonded interactions (cation-π, hydrogen bonds, steric clash, etc…). Create molecular surfaces and analyze surface properties such a hydrophobic and electrostatic potentials. Analyze surface patches to understand local hydrophobic and polar properties. Compare multiple structures to understand differences in affinity and structural variability. Highlight potential reactive sites for oxidation and deamidation. Visualize and rank hot spots using knowledge-based potentials and evaluate the non-linear Poisson-Boltzmann equation to evaluate electrostatic preferences in order to rationalize interactions and potential sites for mutagenesis.

Predict protein-protein binding poses. Generate high quality docked protein structures using a coarse-grained bead model in conjunction with Fast-Fourier Transform (FFT) followed by all atom minimization. Focus the sampling space by using knowledge-based rigid body docking. Automatically detect antibody CDR sites to restrict the search space. Generate and analyze protein-protein interaction fingerprints to determine key residues implicated in binding.

Build 3D antibody structures or fusion proteins (including multi-domain models) from amino acid sequence by assembling domain fragments of experimentally determined backbone structures from one or more templates. Use specialized protocols for antibody modeling [Almagro 2011]. Specify a customizable loop dictionary for knowledge based loop modeling. The homology models are scored with various scoring functions including MM/GBVI. Include environment units such as scFv, Fc or antigen fragments in the structural template for induced fit.

Visualize high valued hydrophobic and charged protein patches to rationalize surface properties and assess aggregation prone regions. Apply protein patch descriptors in QSAR and QSPR models for predicting and modulating protein properties such as solubility and viscosity. Use protein patches for detecting potential binding sites or mapping epitopes.

Calculate a comprehensive set of sequence and structure based physical properties such as pI, zeta potential, mobility, dipole moment, etc. for QSPR modeling. Use the predicted properties in conjunction with preliminary experimental data to rationalize stability and aggregation at a given pH. Calculate properties for an ensemble of mutants to identify and predict physical property trends on a relative scale.

MOE - Protein Engineering Explore and compare mutant series against a wild type with a unified protein engineering application. Conduct Alanine Scanning to systematically explore affinity. Assess protein stability and optimize unstable regions by identifying disulfide bridging opportunities through Cysteine Scanning. Rationalize and perform single point or multiple mutations via Residue Scanning to assess and advance lead candidates. Use Sequence Design to search all possible multiple mutations to determine an optimal sequence. Easily identify residues prone to natural mutation, based on single nucleotide polymorphism, using Resistance Scanning. Automatically generate ensembles using molecular dynamics or LowModeMD to estimate ensemble averaged properties.

Perform single point mutations and discover amino acid accessibility with MOE's Rotamer Explorer. Predict the structure of amino acid mutations in a 3D protein structure and candidate rotamers using an energy-based scoring function. Visualize and analyze new interactions and properties using MOE's graphical interface.

Visualize and modify structures at the residue level with an integrated sequence editor. Edit sequence information by cutting and pasting residues for loop grafting or build sequence, proteins, DNA or PTM structures. Mutate residues and evaluate rotamers with the Rotamer Explorer. Find optimal alignments of protein sequences and structural superposition using CCG's unique technology. Automatically annotate antibodies and apply alignment constraints for optimal superposition. Use the Sequence Editor to adjust alignments interactively. Dynamically color residues by function, sequence similarity or structural proximity.

Apply a streamlined process for structure preparation and optimization. Run molecular dynamics (MOE or NAMD) to evaluate stability and gross motions in loops or solvent. Run LowModeMD for generating a ensemble of conformations for protein loops, domains or peptides. Include explicit solvent with little overhead.


References

[Almagro 2011] Almagro, J.C., Beavers, M.P., Hernandez-Guzman, Maier,J., Shaulsky, J., Butenhof, K., Labute, P., Thorsteinson, N., Kelly, K., Teplyakov, A., Luo, J., Sweet, R., Gilliland, G.L.; Antibody Modeling Assessment; Proteins: Struct. Func. Bioinf. 79 (2011) 3050–3066.

[Long 2010] Long, W.F., Labute, P.; Calibrative Approaches to Protein Solubility Modeling of a Mutant Series using Physicochemical Descriptors; J. Comput. Aid. Mol. Des. 24 (2010) 907–906.