Protein Annotation / Protein Patches / Virtual Mutagenesis / Antibody Homology Modeling / Protein Properties / Developability

The workshop covers the application of computational tools for modeling the structures of antibodies, for humanization, and for optimization of properties to enhance developability. Examples will include the identification of glycosylation sites and analysis of correlated pairs using a specialized antibody database. The calculation of protein properties and their optimization to facilitate developability as a product will also be covered.

MOE Databases / Descriptors / Fingerprints / QSPR Modeling / Pharmacophore Modeling / Template-Forced Docking / Scaffold Replacement / MedChem Transformations

The course covers the suite of MOE applications which can be applied to small-molecule virtual screening. Topics include the preparation of small molecule databases for virtual screening, filtering databases based on substructure matching and property values, building QSAR/QSPR models and fingerprint similarity models as database filters, pharmacophore query creation and searching, and small-molecule docking. These tools are used in conjunction to present a complete virtual screening workflow. The creation of de novo structures using the MOE Scaffold Replacement and MOE Medchem transformation applications is also covered.

Mixed methods / Quantum Mechanics / Molecular Mechanics / Gaussian / ONIOM

Detailed understanding of electronic effects are critical for properly understanding enzymatic reactions, or processes that occur in solution (as just two examples). However, it remains impractical to apply quantum mechanical (QM) approaches to such large biological systems. As a compromise between computational cost and predictive accuracy, mixed method approaches allow us to rigorously partition a system into regions that are treated classically (using molecular mechanics) and (typically) smaller regions that are treated using QM. This partitioning scheme allows the user to focus the more realistic electronic treatment to where it is most needed, providing the practical balance of accuracy and timeliness. The ONIOM scheme, as implemented in the Gaussian electronic structure package, allows for the partitioning of a system into multiple regions, each of which can employ a different level of theory. In MOE 2020 we have created a simple and intuitive interface to set up ONIOM calculations. Using MOE’s powerful ‘selection language’, the assignment of layers is trivial, as is the creation of all required Gaussian input files. These calculations can leverage the new high-performance compute framework available in MOE 2020 to seamlessly be executed, either locally or remotely, using MOE as a simple front-end to your computational queuing system. During this webinar we will provide a brief theoretical orientation to the ONIOM method, followed by a demonstration of how to set up, execute, and analyze ONIOM calculations directly from within the MOE platform.

Protein-Protein Docking / Molecular Surfaces / Protein Patches / Interaction Fingerprints / Clustering / Epitope Analysis

The MOE Protein docking application is used to map epitopes and other protein-protein interfaces (PPI). This automatically calculates a PPI fingerprint for each pose. The poses are clustered using the fingerprint, and epitope residues are identified from the top ranking clusters. The poses can then be annotated in the MOE Window, for browsing through all the top epitopes.

Macromolecular repository / 3D query searching / Pocket similarity / Display electron density / Central repository / Specialized protein databases

PSILO® is a web-based platform for the deposition and analysis of macromolecular structural information. The workshop will describe the application of PSILO® for mining biomolecular data. Approaches to query generation and search result navigation in PSILO will be covered in detail; for example, 3D contact searching, and protein pocket similarity searching. The PSILO and MOE platforms are tightly integrated, and the ability to perform PSILO search queries directly from within MOE will also be described.

Structure Preparation / Sidechain Rotamer Exploration / Electron Density Maps / X-Ray / CryoEM / Solvent Analysis with 3D-RISM

The course will cover methods for evaluating, analyzing and refining protein models derived from electron density data. Topics related to protein structure preparation and side-chain conformational analysis and placement will be discussed. Visualization and interpretation of electron density maps (X-ray/CryoEM) for assessing protein models will be described. The 3D-RISM method for predicting and refining the placement of solvent molecules in protein models will also be presented.

Cloud / AWS / HPC / High-Throughput Screening / Large Scale Calculations / SLURM / Amazon Cluster

Running MOE on the AWS cloud might appear intimidating. It involves: installing the server and software, configuring a workload manager, data preparation, data transfer, job submission and data retrieval. In this webinar we will start from a newly created AWS account and show how easy it is to install an elastic compute cluster ready for MOE. Next we will connect the AWS cluster to the MOE HPC infrastructure to submit jobs from different applications (Dock, Protein Design, Ensemble Protein Properties, etc.) right from the graphical user interface of your local MOE installation. We will monitor the jobs and retrieve the results once the calculations have been completed. In the last part of the webinar we then install a single instance of MOE on AWS and use the GUI via the browser.

Solvent Analysis / 3D-RISM / Lead Optimization / Water Placement

The investigation of water molecule placements, both real and potential, around a protein-ligand complex can provide possible routes for enhancing ligand affinity. For example, calculations using the 3D-RISM method on a crystallographically determined complex enable the identification of water molecules whose displacement by a modified ligand may enhance binding. The theory behind the method, its application and validation will be presented.

Homology Modeling / Protein Properties Calculations / QSAR/QSPR Modeling / Protein Patch Analysis

The course will cover a typical protein/biologics solubility prediction workflow. First, homology models will be generated for a series of Adnectin sequences. Protein properties will then be calculated for the modeled Adnectins, and the correlation between different properties and experimental solubility data will be investigated. Next, QPSR models will be generated to predict solubility based on the calculated protein properties. Finally, Protein Patch Analysis will be used visualize the differences between structures with varying solubility.

Protein Alignments and Superposition / Loop and Linker Modeling / Homology Modeling / Protein- Protein Docking

The course covers methods for aligning protein sequences, superposing structures, homology modeling fusion proteins and conducting protein-protein docking. In particular, an approach for aligning and superposing multiple structures will be described for determining structural and surface protein variations in relation to protein property modulation. A method for grafting and refining antibody CDR loops as well as using a knowledge-based approach to scFv fusion protein modeling using the MOE linker application will be described. An approach to generate homology models of a murine antigen structure from a human template as well as protein-protein docking of an antibody to an antigen will be discussed.

Docking / Pharmacophore Modeling / Fragment-Based Design / Scaffold Replacement / Protein-Ligand Interaction Fingerprints (PLIF)

This workshop will cover some advanced workflows for structure-based design in drug discovery projects. The application of pharmacophores in the context of protein-ligand docking and scaffold replacement will be included, as will the generation and analysis of protein-ligand interaction fingerprints (PLIF). Participants will therefore experience a broad range of computational tools that can be brought to bear for lead generation and optimization.

Scaffold Replacement / Fragment Linking / Ligand Growing / R-Group Screening / Medicinal Chemistry Transformations / Combinatorial Fragment Libraries / Pharmacophore Models / Fragment Databases

Fragment-based drug design (FBDD) is a key approach in the discovery of high-quality drug candidates. As a compliment to biophysical FBDD methods, insilico FBDD uses structure-based approaches to rapidly design and screen large libraries of virtual compounds, allowing for the exploration of a much larger chemical space. The webinar will describe insilico FBDD methods ranging from combinatorial fragment design to scaffold-hopping in the receptor active site, along with approaches for fragment linking and growing. A method for generating a series of closely related derivatives through the reaction-based Combinatorial Library and Medicinal Chemistry Transformations applications in the MOE software will be presented. The use of pharmacophore models and 2D/3D descriptors to guide insilico FBDD processes will also be discussed.

Conformational Search / Molecular Dynamics / Macrocycles / Loop Modeling

We present a method for conformational search of complex molecular systems such as macrocycles and protein loops. The method is based on perturbing an existing conformation along a molecular dynamics trajectory using initial atomic velocities with kinetic energy concentrated on the low-frequency vibrational modes, followed by energy minimization. A novel Chebyshev polynomial filter is used to heavily dampen the high-frequency components of a randomly generated Maxwell−Boltzmann velocity vector. The method is very efficient, even for large systems; it is straightforward to implement and requires only standard force-field energy and gradient evaluations. The results of several computational experiments suggest that the method is capable of efficiently sampling low-strain energy conformations of complex systems with nontrivial nonbonded interaction networks.

Structure preparation / Non-natural amino acids / Conformational searching / Distance restraints / Peptide-protein docking / Protein-ligand interaction fingerprints

The course covers methods for analyzing and optimizing peptide-protein interactions in the active site. Topics related to peptide-protein structure preparation, peptide sequence optimization using natural and non-natural acids and conformational analysis will be discussed. Peptide-protein docking and protein-ligand interactions to analyze contact points will be described. The course will also cover advanced conformational searching using distance restraints.

Molecular Databases, Conformational Searching, Small-Molecule Superpositions / Flexible Alignment / Pharmacophore Modeling and Searching / Molecular Fingerprints

The course will cover some essential in silico methods needed for guiding drug discovery projects in the absence of a protein structure. Molecular alignments and conformational analyses of molecules from a congeneric series will be used to investigate the impact of ligand substituents. A pharmacophore model will be created based on a pair of superposed ligand structures, and then used to identify new compounds matching the required pharmacophore features. Other topics covered will include fingerprint-based similarity searching and manipulation of MOE databases.

Protein Engineering / Protein Properties / Developability / Hot Spot Analysis

The workshop covers approaches for structure-based antibody design and includes protein-protein interactions analysis, in silico protein engineering, affinity modeling and antibody homology modeling. The interaction of a co-crystallized antibody-antigen complex will be studied by generating and examining the molecular surfaces and visualizing protein-protein interactions in 3D and 2D. Antibody properties will be evaluated using specialized calculated protein property descriptors and analyzing protein patches.