Schrdinger Life Sciences 2013 Major New Features & Enhancements

We are very excited about this releaseit contains a number of new features and improvements, largely in response to user feedback. Highlights include: Improved performance and stability Faster structure browsing in the Project Table Smaller and more robust project files Improved Workspace performance Desmond GPU support Streamlined operations in Maestro One-click job launching Easy navigation through structures with the new docked Entry List New searchable Task Tree for finding tasks and applications In addition to improvements to the Maestro and BioLuminate interfaces, key scientific enhancements include: New covalent docking method Peptide docking mode Improved metal coordination in docking Structure-based membrane permeability Sequence-based SAR for PPIs Peptide cross-linking tool QM-based pKa prediction with new shell method Improved induced-fit docking (IFD) Improved cysteine scanning sampling and scoring New antibody modeling options Additional antibody humanization options Improved aggregation hotspot analysis

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Schrdinger Life Sciences 2013 Major New Features & Enhancements

Table of Contents
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 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

Peptide-based SAR Cysteine Scanning Aggregation Hotspot Analysis Antibody Modeling Antibody Humanization

Graphics Usability Bug Fixes

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Schrdinger Life Sciences 2013 Major New Features & Enhancements

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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Schrdinger Life Sciences 2013 Major New Features & Enhancements

Ligand Docking (Glide)

Recognize and reward formation of intramolecular ligand H-bonds Metal coordination constraints to more accurately reproduce ligand-metalloprotein interactions Expand ligand conformational sampling with enhanced sampling option Docking mode to improve native pose reproduction of docked polypeptides Larger grid dimensions allowed Score input pose Dock ligands from multiple input files in a single Glide job (command line only) Return poses based on GlideScore cutoffs (command line only) Option to eliminate dependence of results on input conformation and platform

Induced Fit Docking

Improved initial docking stage for more pose diversity Automated trimming / mutating of highly flexible side chains to improve initial docking Support for Glide core constraints New scoring function

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 (Phase)

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 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) Fixed bug that caused database screens that attempt to match a minimum of two hypothesis sites to fail

Shape Screening
Pin down the locations of one or two atoms while optimizing the overall alignment (command line only) 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)

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Schrdinger Life Sciences 2013 Major New Features & Enhancements

Field-Based QSAR

A new aromatic Gaussian field type is provided to model - interactions Electrostatic fields may now be generated from user-input partial charges The percentage of a structures field values that lie outside the training set domain is now reported to help assess the reliability of its predicted activity

Cheminformatics (Canvas)
New substructure filters for identification (and removal) of pan assay interference compounds (PAINS) Fingerprints of two or more structures may be merged to create a new row that contains a combined Modal (union of bits) fingerprint Views may be created from selected columns R-Group Analysis provides a new Estate QSAR method with model visualization Skipping duplicate structures on import now supports matching against different tautomeric forms

Molecular Dynamics (Desmond)

New radial distribution function MD analysis interface Restarting from checkpoint file for REMD Improvements to metadynamics 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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Schrdinger Life Sciences 2013 Major New Features & Enhancements

Quantum Mechanics (Jaguar)

B3LYP-MM method accounting for dispersion, -cation, and H-bond interactions 2nd derivatives of B95 correlation functional Extended and improved parallelization of key modules B3LYP-LOC method accounting for non-dynamical correlation B3LYP-DBLOC method predicting energetics of some 3d metal complexes ulg correction for non-covalent interactions Analytic and pseudospectral Rappoport basis set Automatic assignment of vibrational frequency scaling factors Tools (via keyword in the input file) to help with SCF and geometry optimization convergence Tools (via keyword in the input file) to help with preventing chemical reactions during geometry optimizations 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 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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Schrdinger Life Sciences 2013 Major New Features & Enhancements

Protein Refinement (Prime)

New rigid body minimization 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 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 New covalent ligand sampling method conformational optimization of a covalently bound ligand along with its environment New local optimization optimization of a ligand and its environment via side chain prediction and minimization 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 (PrimeX)

New launch panel for X-Ray Refinement Resolved difficulty handling some loops in real-space loop refinement Improved compatibility of PrimeX-generated mtz map files with other programs Resolved problems updating temperature factors for some job types Map calculation improved for ligand placement Truncated side chains handled more efficiently Standardized residue and atom names for all waters Added parameters for Cd2+ ions in simulated annealing Force field choices provided for PrimeX jobs Improved speed of polish workflow by 20-50% Improved H-bond optimization in polish workflow, including use of PROPKA for amino acid protonation Added extensive error checking at start of polish workflow with instructive error messages Modified the polish workflow to work in Windows Improved selection of most stable complex in polish workflow by using Glide Docking Score

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Schrdinger Life Sciences 2013 Major New Features & Enhancements

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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Schrdinger Life Sciences 2013 Major New Features & Enhancements

Peptide sequence-observables SAR Major improvements to cysteine scanning panel 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 Antibody modeling new functionality 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 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) 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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Schrdinger Life Sciences 2013 Major New Features & Enhancements

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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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