Schrödinger Life Sciences 2013 Major New Features & Enhancements We are very excited about this release—it contains a number of new features and improvements, largely in response to user feedback. Highlights include: • improvements to the performance, stability, and size of Maestro projects, and • major usability enhancements to Maestro, such as: ◦◦ streamlined job starting ◦◦ a new interface for managing structure entries, and ◦◦ a new panel that makes accessing applications and tasks significantly easier We have also made a number of important usability improvements to the Biologics Suite. In addition to improvements to the Maestro and BioLuminate interfaces, we have also made a number of improvements to the science, including: • New Covalent Docking method that is a major improvement over the previous version • Significantly improved Glide docking accuracy for metalloproteins • Major improvement to the QM-based pKa prediction module in Jaguar • A large number of new protein and ligand refinement methods in Prime • Scientific advances in quantum mechanics methods
Click on a topic in the table of contents below to jump to specific features and enhancements covered in this document.
Maestro Graphical Interface Ligand Preparation and Conformation Generation Rule-based and QM-based pKa Prediction Covalent Ligand Docking Ligand Docking (Glide) Induced Fit Docking ADME Prediction Pharmacophore Modeling Shape Screening Field-Based QSAR Cheminformatics Molecular Dynamics R-Group Analysis Quantum Mechanics Core Hopping Structure-Based P450 Site of Metabolism Prediction Protein Refinement Protein X-Ray Refinement Workflows & Pipelining [KNIME Extensions]
Graphics Usability Bug Fixes
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Maestro Graphical Interface • New job starting and monitoring controls (jobs start without intermediate dialog) • New Task Tree interface – customizable and searchable interface to all tools and applications • New Entry List – simplified and dockable version of the Project Table • 2x Speedup of import of PDB and SD files • 2x Speedup of writing selected entries when jobs are started • Improved performance and robustness of Projects • Reduced Project size • Feature to include multiple entries with the arrow keys (e.g., when reviewing pairs of poses) • Internal property names can be set in addition to visible property names • Coordinate axes display • Anaglyph (red/cyan) stereo – works on any display • Full set of elements directly available from the builder toolbar Draw and Element tools • UFF cleanup can be applied to only selected atoms • BLAST genome filtering for local searches in the Multiple Sequence Viewer • Display of full information for BLAST hits in Multiple Sequence Viewer
Ligand Preparation and Conformation Generation • Explicit tracking of structures that could not be processed [LigPrep] • Automatic retry for failed subjobs [LigPrep] • Specialized templating for macrocycles [MacroModel] • Optional on-the-fly ring templating [Glide, ConfGen, LigPrep, Phase] • Additional ring templates [Glide, ConfGen, LigPrep, Phase] • Better prioritization of protonation states in rule-based method [Epik]
Rule-based and QM-based pKa Prediction • Significantly improved coverage of QM-based method [Jaguar pKa] • pKa uncertainties in rule-based method now based upon similarity with training set molecules [Epik] • More robust coverage of rule-based method [Epik]
Covalent Ligand Docking • Entirely new method based on Glide and Prime • Support for large number of common covalent docking chemistries • Prediction of both binding conformation and apparent affinity
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Ligand Docking (Glide) • Recognize and reward formation of intramolecular ligand H-bonds [Glide] • Metal coordination constraints to more accurately reproduce ligand-metalloprotein interactions [Glide] • Expand ligand conformational sampling with enhanced sampling option [Glide] • Docking mode to improve native pose reproduction of docked polypeptides [Glide] • Grid generation can be run on GPGPU to reduce grid generation time significantly [Glide, IFD] • Larger grid dimensions allowed [Glide] • Score input pose [Glide] • Dock ligands from multiple input files in a single Glide job (command line only) [Glide] • Return poses based on GlideScore cutoffs (command line only) [Glide] • Option to eliminate dependence of results on input conformation and platform [Glide]
Induced Fit Docking • Improved initial docking stage for more pose diversity [IFD] • Automated trimming / mutating of highly flexible side chains to improve initial docking [IFD] • Support for Glide core constraints [IFD] • New scoring function [IFD]
ADME Prediction • Return all ligand structures in output structure file even for ligands that could not be processed [QikProp] • New physics-based method for predicting membrane permeability and LogD – incorporates conformational search and Epik state penalties [Prime]
Pharmacophore Modeling • New command line ligand superposition tool (phase_align_core) to force the alignment of a common core while conformationally sampling the remainder of the structure [Phase] • New option that allows different types of complementary aromatic interactions (stacking, T-shaped, etc.) to be considered simultaneously when creating a pharmacophore hypothesis from a ligand-receptor complex (phase_complex) [Phase] • Fixed bug that caused database screens that attempt to match a minimum of two hypothesis sites to fail [Phase]
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Shape Screening • Pin down the locations of one or two atoms while optimizing the overall alignment (command line only) [Phase Shape] • When using multiple shape queries, a new option is available to skip to the next screening structure when any of the shape queries satisfies the similarity filter (command line only) [Phase Shape]
Field-Based QSAR
• A new aromatic Gaussian field type is provided to model π-π interactions • Electrostatic fields may now be generated from user-input partial charges • The percentage of a structure’s field values that lie outside the training set domain is now reported to help assess the reliability of its predicted activity
Cheminformatics • New substructure filters for identification (and removal) of pan assay interference compounds (PAINS) [Canvas] • Fingerprints of two or more structures may be merged to create a new row that contains a combined “Modal” (union of bits) fingerprint [Canvas] • Views may be created from selected columns [Canvas] • R-Group Analysis provides a new Estate QSAR method with model visualization [Canvas] • Skipping duplicate structures on import now supports matching against different tautomeric forms [Canvas]
Molecular Dynamics • New radial distribution function MD analysis interface [Desmond] • Restarting from checkpoint file for REMD [Desmond] • Improvements to metadynamics [Desmond] ◦◦ New collective variable supported • RMSD • symmetry corrected RMSD • WHIM1 & WHIM2 • Radius of Gyration ◦◦ Well-tempering supported for improved convergence • Added GPU support for Desmond
R-Group Analysis • Better automatic core/R-group decomposition – R-group similarity accounted for when aligning multiple input structures; also, new option to avoid broken rings in automatically generated cores [RGA] • E-State RQSAR – new method uses e-state atom types to assess positional effects on free-energies of binding for more detailed analysis than the existing pharmacophoric RQSAR method [RGA] • Improved RQSAR interface [RGA, Maestro, Canvas]
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Quantum Mechanics
• B3LYP-MM method accounting for dispersion, π-cation, and H-bond interactions [Jaguar] • 2nd derivatives of B95 correlation functional [Jaguar] • Extended and improved parallelization of key modules [Jaguar] • B3LYP-LOC method accounting for non-dynamical correlation [Jaguar] • B3LYP-DBLOC method predicting energetics of some 3d metal complexes [Jaguar] • ulg correction for non-covalent interactions [Jaguar] • Analytic and pseudospectral Rappoport basis set [Jaguar] • Automatic assignment of vibrational frequency scaling factors [Jaguar] • Tools (via keyword in the input file) to help with SCF and geometry optimization convergence [Jaguar] • Tools (via keyword in the input file) to help with preventing chemical reactions during geometry optimizations [Jaguar] • A new interface panel for VCD spectra [Maestro] • A new panel and workflow for ∆H of formation [Maestro] • Batch calculations can now be run in parallel [Jaguar] • A new QM profile for Maestro [Maestro] • Improved interface for geometry constraints [Maestro]
Core Hopping • Variable linkers (no longer restricted to only methylene linkers) • Joining rules – chemically based joining rules to avoid core-linker-R-group connections that are synthetically or metabolically undesirable • Better geometric sampling – corrected issues in previous releases that were passing over good core candidates • Better core libraries – cores are now restricted to a maximum Smallest Set of Smallest Rings (SSSR) ring size of 9; discards core candidates based on an expanded list of undesirable substructures
Structure-Based P450 Site of Metabolism Prediction • Significantly improved accuracy for 2D6 and 2C9 isoforms • Supported on the Cloud
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Protein Refinement • New rigid body minimization [Prime] ◦◦ Specification of any arbitrary set of rigid body substructures ◦◦ Optional specification of a “free moving” (non-rigid) region • New Monte Carlo side chain prediction – returns multiple low energy solutions [Prime] • New Monte Carlo minimization – Monte Carlo sampling of a ligand and its environment using multiple different move types: (1) side chain rotamer changes; (2) rigid-body ligand translations and rotations; (2) hybrid MD [Prime] • New covalent ligand sampling method – conformational optimization of a covalently bound ligand along with its environment [Prime] • New local optimization – optimization of a ligand and its environment via side chain prediction and minimization [Prime] • New Cartesian restraints • New chloroform solvation model • New protein reliability reporting tool – quickly and easily visualize whether a protein structure is sufficiently reliable for use in modeling • New Prime energy visualization tool ◦◦ Visualize atom-level contributions to Prime Energy, MM-GBSA, WM-MM ◦◦ Visualize individual terms in the force field and solvation model ◦◦ Visualize solvent accessible surface area • New protein splicing tool – easily splice protein segments from one structure to another • Improved support for non-standard amino acids • Support for batch processing of structures from the graphical interface [Maestro]
Protein X-Ray Refinement • New launch panel for X-Ray Refinement [Maestro, PrimeX] • Resolved difficulty handling some loops in real-space loop refinement [PrimeX] • Improved compatibility of PrimeX-generated mtz map files with other programs [PrimeX] • Resolved problems updating temperature factors for some job types [PrimeX] • Map calculation improved for ligand placement [PrimeX] • Truncated side chains handled more efficiently [PrimeX] • Standardized residue and atom names for all waters [PrimeX] • Added parameters for Cd2+ ions in simulated annealing [PrimeX] • Force field choices provided for PrimeX jobs [PrimeX] • Improved speed of polish workflow by 20-50% [PrimeX] • Improved H-bond optimization in polish workflow, including use of PROPKA for amino acid protonation [PrimeX] • Added extensive error checking at start of polish workflow with instructive error messages • Modified the polish workflow to work in Windows [PrimeX] • Improved selection of most stable complex in polish workflow by using Glide Docking Score [PrimeX]
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Workflows & Pipelining [KNIME Extensions] • Based on latest version of KNIME (v2.7) • Infrastructure improvements ◦◦ Environment for a standalone installation configurable in the preferences ◦◦ Generation of the command to be run in batch based on node annotations; enables workflows to be easily run in Seurat ◦◦ Parameter flow variables can use any backend command line option that is not exposed in the node configuration panel ◦◦ Workflow examples available in the installation • New nodes ◦◦ Workflow list – lists the nodes and workflows in the workspace ◦◦ SiteMap ◦◦ PyMOL • Node functionalities ◦◦ KNIME in Maestro – input structures from files ◦◦ More nodes input and output PDB and SDF (e.g., Glide ligand docking, Assign bond order, Split by structure) ◦◦ Prime MM-GBSA and Glide ligand docking – Extract automatically the generated properties ◦◦ Parameter flow variable capability hooked up to Glide Ligand Docking, Prime, Protein Preparation Wizard, SiteMap, some Jaguar, MacroModel, and Canvas nodes. ◦◦ Chemistry External Tool – with optional input/output ports, access to the flow variables by name, basename, and other new keywords ◦◦ Many bug fixes and minor improvements
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• Peptide sequence-observables SAR [BioLuminate] • Major improvements to cysteine scanning panel [BioLuminate] ◦◦ Improved sampling when creating disulfides ◦◦ Improved scoring function ◦◦ Ability to monitor MD trajectory to look for potential pairs ◦◦ Added numerous filters on candidate selection • Improvements to aggregation hotspot analysis – create sortable table that identifies residues contributing to hotspots [BioLuminate] • Antibody modeling – new functionality [BioLuminate] ◦◦ Ability to include bound antigen structure during the modeling process ◦◦ Ability to use separate templates for light and heavy chain during framework generation (command line only) • Antibody humanization [BioLuminate] ◦◦ Ability to carry out CDR-grafting/framework replacement ◦◦ Automated identification of clash interface residues post grafting • Ability to carry out humanization by using human framework and back mutating to accommodate CDR • Cross link tool – ability to generate a peptidic cross-linker to join two peptide chains (N/C terminus connections) [BioLuminate] • New protein reliability reporting tool - quickly and easily visualize whether a protein structure is sufficiently reliable for use in modeling • New protein chimeric model tool - easily create chimeric models by splicing together segments from multiple structures
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Graphics • Faster overall real-time rendering • Faster real-time rendering of fonts, selection indicators, ramps, ellipsoids, slices, menus, and more • Added arbitrary image backgrounds for both rendering and ray tracing
Usability • Most settings are now documented in the Settings > Edit All GUI • Added menu item to color by representation • Added sweep angle setting with “Program > Scene Loop” Nutate/Rock • Added bz2 support for reading PDB/MAE/MOE/... files • Added support for width/height units in png command • Shortcut auto-completion with exact prefixes now shows all options • Increased performance on the iterate/alter commands
Bug Fixes • Restored Space Navigator 3D Input (on Mac) • Restored multi-threaded object building • Better tracking of hydrogens when editing with the Builder • Alignment objects from “super” now contain nitrogens • Writing PDB files ◦◦ END before ENDMDL ◦◦ Always right justify residue name when saving to PDB • Fixed crash when loading structures with connect • Fixed feedback errors
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