v 6.1.4 September 2023¶
In this release we have mainly focused on minor bug fixing.
Search keywords have been added to the Induced-Fit Posing (IFP) Floes and the Short Trajectory MD with Analysis Floe.
In the Induced-Fit Posing (Confined) Floe, site residue matching between proteins for the site similarity measures has been improved.
v 6.1.2 July 2023¶
The Gromacs MD engine to run MD and Free Energy has been updated to the 2022.3 release. This update should have better MD performance in addition to bug fixing.
In NES, edges involving stereo center inversion are now supported. Specifically, NES edges involving changes in chirality (both R/S inversion and achiral/chiral site introduction) are now implemented correctly. Prior to this bug fix, directed edges with R->S chiral inversion were implemented as R->R and the reverse S->R transitions were implemented as S->S. This previous behavior led edges connecting two enantiomers to incorrectly estimate relative binding free energies as approximately 0 kcal/mol. Moreover, prior to this bug fix, directed edges representing achiral->chiral conversions may or may not have introduced the intended chirality (though chiral->achiral transitions were correct).
Floes for Induced-Fit Posing (IFP), a three-step protocol for the correct prediction of the binding pose of a ligand that requires induced-fit of receptor binding site residue side chains, have been added.
Induced-Fit Posing Prep: Pruning reference receptor for docking This Floe prunes the side chains in the binding site of the reference receptor for docking. The output datasets can be used as an “Optional Pruned Reference Receptor Input Dataset” in the “Optional Inputs” section of the Induced-Fit Posing (Confined) Floe.
Compare IFP Results to Target Receptor This Floe performs the comparison of the IFP results with the target receptor bound to the docking ligand and generates a Floe report.
The Edge Mapper for RBFE calculations has been patched to remove dangling nodes not involved in cycles
The Bound Protein-Ligand MD, Short Trajectory MD with Analysis, Solvate and Run MD Floes now run MD simulations in chunks by using a Floe cycle topology to overcome the AWS session limit and make long MD simulations possible in Orion.
MutatedInputChecker This Cube checks if an optional pruned reference receptor is given.
ActiveSiteDetectCube This Cube finds an active site from the MDComponents object and saves a list of the active site atom indices.
MutateActiveSiteCube This Cube prunes receptor binding site side chains to ALA to allow more space in the binding site, avoiding heavy clashes during docking. The binding site is defined based on the cut-off distance from the cognate ligand of the input reference receptor.
SetMapIdxCube This Cube sets the reaction map index property of each atom of the primary molecule to its original atom index.
ResetAtomIdxCube This Cube sets the AtomIdx of each atom of the primary molecule to MapIdx.
AdditionalPOSITSwitch This Cube switches whether to run an additional POSIT with an additional OEDocking method or not.
IFPPositCube This Cube generates relaxed high probability poses for ligands that are analogs of the ligand in the receptor. This cube is suitable for pose generation when working with multiple receptors.
POSITGatheringCube This Cube creates one record per ligand for post-processing. The primary molecule of the per-ligand record is the multi-conf mol of the Posit poses.
AddReceptorTypeCube This Cube sets the receptor type field to the record.
PoseMMPBSACube This Cube computes the MMPBSA score and BintScore from the last frame of the MD stage.
MinPoseGatheringCube This Cube creates one record per ligand for post-processing. The primary molecule of the per-ligand record is the multi-conf mol of the minimized poses.
ClusterCube This Cube runs clustering for the deduplication of the poses.
DockingCheckerCube Given a target receptor to compare, this Cube checks the goodness of the posing results.
IFPIDSettingCube This Cube sets the integer ID for each simulation flask as well as a descriptive title string. If the input molecule on a record has multiple conformers, these are split into singles, each with its own ID. If a complex will be formed, this Cube should be used on ligands before forming the complex.
IFDMinimizeCube This Cube performs multi-layered restrained energy minimization on the docked pose/reference receptor conformation.
ComputeScoreCube This Cube computes the IFP score.
ComputeInitScoreCube This Cube computes the step 1 IFP score.
IFPBintScoreInitialPoseAndTrajectory This Cube computes the BintScore and iBintScore over the selected frames of the induced-fit trajectory.
IFPConcatenateTrajBintScoreCube In this Cube, induced-fit trajectory BintScores and iBintScore are concatenated based on preexisting per-conformer vectors.
IFPClusterPopAnalysis This Cube analyzes the induced-fit trajectory clusters in terms of their occurrence, size, and proximity to the starting pose(s).
IFDOutputPrepCube This Cube takes the last coordinates from the MDDataRecord and saves the updated DU in the “InducedFitPoseDU” field and updates the primary molecule coordinates.
IFPRankSetting This Cube sets the IFP Rank field and resets the primary molecule title with the suffix “_IFP_rankN”.
IFPOrderOutputRecords This Cube orders the records of the output dataset based on the IFP Rank field.
ExtractClusAvgFromTraj This Cube extracts a main cluster average from the MD trajectory analysis results.
PLAnalysisInputCheckerCube This Cube checks if the input dataset is the output dataset of MD Analysis Floes. If True, it emits the input to the failure port.
SolvateMDInputCheckerCube This Cube checks if the input dataset is the output dataset of MD Floes. If True, it emits the input to the failure port.
v 6.0.3 April 2023¶
The MD API Dataset Converter Floe has been updated to support the conversion from datasets serialized by using pickle to new datasets, where the serialization/deserialization is handled by using JSON. The MD Floes have been updated to automatically perform the dataset conversion, and no action is required by the users. However, dataset conversion is required for old datasets produced by custom customer Floes.
The Plain Molecular Dynamics Floe, which runs MD simulations in chunks by using a Floe cycle topology to overcome the AWS session limit and make long MD simulations possible in Orion, no longer pins instance type and spot policy. Users can now choose cheaper and faster instances for long MD simulations.
Concatenate Trajectory BintScore Components Cube. This Cube concatenates protein-ligand trajectory BintScores based on preexisting per-conformer vectors.
v 5.6.1 December 2022¶
Improved Edge Mapper.
Dual-trajectory ensemble MMPBSA support in the Short Trajectory MD with Analysis Floe.
The Edge Mapper for RBFE calculations Floe has two improvements:
Alchemical changes between ligands of different formal charges are now allowed. No charge-correction is attempted along the edge at this time; this will change soon.
Edge scores are calculated for user provided mapper files.
The Short Trajectory MD with Analysis Floe now computes both the single-trajectory and dual-trajectory ensemble MMPBSA scores during the trajectory analysis.
2-traj MMPBSA Cube. This Cube computes the dual-trajectory ensemble MMPBSA.
The OE Mapper Cube has been improved. Now the user provided mapper files are displayed with the calculated edge scores. In addition, edges between ligands with different charges are now allowed although no charge corrections are attempted at this stage during the NES switching. Our testing shows the uncorrected results are still reasonable though we will put in the correction soon.
The Affinity Plot Cube has been updated to add the correlation plot of dual-trajectory ensemble MMPBSA vs. experimental data to the existing single-trajectory ensemble MMPBSA and BintScore correlations vs experiment.
v 5.5.3 September 2022¶
In this release we have mainly focused on bug fixing. Improvements have been done of the Chimera MCSS calculation, ligand isomeric SMILES matching, and Chimeric molecule frame alignment.
The RBFECEdgeGathering Cube has been improved for better handling of ligand matching, by using isomeric SMILES.
In the NESGMXChimera Cube, the chimera molecule frame alignment, to start the NES switching, has been improved.
Mapper Datasets generated prior to the MD Affinity package version 5.0.5 are no longer supported by the NES Floes, and they must be recreated by using the Edge Mapper for RBFE calculations Floe
v 5.5.0 July 2022¶
In this release the major change is the harmonization of the Short Trajectory MD with Analysis (STMD) Floe with Non-Equilibrium Switching (NES). Before this, after running STMD, for NES another equilibration run had to be made to get both ligand bound and unbound simulations of adequate length (6ns) for NES. Now this second equilibration run is unnecessary: STMD now runs both both ligand bound and unbound simulations of 6ns by default, producing output datasets ready for input to NES. Plus, you have the trajectory analysis available for those same equilibrium runs. This 6ns default trajectory for STMD is longer and therefore more expensive than the original 2ns run but we think it is an overall savings by not running a whole extra equilibration step for NES. It is easy to simply reset the new default 6ns back to 2ns if you want to have the faster, cheaper STMD run as before.
A Freeform analysis of the unbound state has been added to STMD.
A new formulation of the BAR overlap metric for the NES work distributions is incorporated into NES edge Floe reports
G4/G5 AWS instances are now supported for OpenMM/GROMACS
All Floes have a new brief parameter and Floe categories.
Compare Experimental Affinity with End Point Analysis Results: This Floe is for comparing the short trajectory MD analysis results (binding affinities predicted using the MMPBSA and BintScore methods) with experimental data.
Short Trajectory MD with Analysis (STMD) has been updated to harmonize with Non-Equilibrium Switching (NES). STMD now runs both both ligand bound and unbound simulations of 6ns by default. Additionally, freeform is now run on the unbound ligand, producing a separate dedicated dataset.
The NES Floes have been updated with a new edge graph Floe report to show the predicted absolute and relative binding affinities. The BAR overlap metric has been added to the NES Floe reports.
The Solvate and Run MD Floe is updated to support apo protein simulations.
Bound and UnBound Splitting Cube. This Cube emits the primary molecule through the bound port and the standard out port to launch separated ligand-bound/unbound simulations.
Unbound FreeForm Cube. This Cube estimates the Gibbs free energy to convert an ensemble of solution conformations into a state where only a single specific conformation is present, and creates XY plot and table image of free energies of conformer ensemble.
Unbound Ligand Preparation Cube. This Cube checks whether the primary molecule (ligand) has a single conformer, and reset the title.
FreeForm Output Ligand Setting Cube. This Cube reads a Freeform record, chooses starting conformations for unbound MD simulations. The conformations are selected based on the probabilities of state associated with each conformation, and users can choose to ignore the Freeform results and use the bio-active conformation instead.
Unbound Traj to OEMol Cube. This Cube converts unbound MD trajectories into a multi-conformer ligand OEMol.
Unbound Traj MMPBSA Cube. This Cube computes molecular mechanics potential energies and solvation energies of the unbound MD trajectory snapshots. The Poisson-Boltzmann and Surface Area methods in the OEZap toolkits are used in the solvation energy estimation. The computed energies in the unit of kcal/mol are attached to the record as per-frame vectors of floats.
Unbound MD Conformer Gathering Data Cube. This Cube gathers conformer records of a ligand and emits a new single record per ligand. The assembly of the conformer records is attached to the record as a record vector.
Unbound Conf Trajs To Ligand Traj Cube. This Cube combines individual conformer trajectory OEMols into single multi-conformer ligand OEMol, in preparation of clustering.
Unbound Cluster Ligand Traj OEMol Cube. This Cube clusters unbound ligand multiconf MD trajectory OEMol.
Ligand Cluster Selection Cube. This Cube selects frames from the clustering analysis.
EdgeFloeReportCube. This Cube generates an edge graph Floe report for the relative and absolute binding affinities.
The OEMapper Cube can also use clustering info to generate the map edges.
The NESAnalysis Cube is now calculating the BAR overlap metric for the work distributions.
v 5.0.5 April 2022¶
The Equilibrium and Non Equilibrium switching Floe now generates a tarball file of key results for download.
The Compare Experimental Affinity with NES Results Floe now generates a tarball file of key results for download.
The NES Recovery Floe now generates a tarball file of key results for download.
The Compare Experimental Affinity with NES Results Floe can now aggregate multiple input datasets to enable users to include the results from previous NES runs.
All the Short Trajectory MD Floes are by default pinning g3 spot instances for reliability.
All the NES Floes are pinning r5.4xlarge and r5.2xlarge Chimera cube instances for better Gromacs compatibility.
MD Analysis Floes are now able to handle any user specified ligand titles, including duplicate ligand titles.
In MD Analysis Floes, generating the results tarball file is now optional.
DDGAggregator cube. The Aggregator cube aggregates the relative binding affinity results produced by Non-Equilibrium Switching runs.
The OE Mapper cube is now sorting the edges by isomeric SMILES.
The NES Analysis cube is now setting the output units.
v 5.0.3 December 2021¶
Edge Mapper for RBFE calculations
Long Trajectory MD supports
OpenFF 2.0 support
Improved Implicit solvent MD
Edge Mapper for Relative Binding Free Energies. A starting edge mapper for RBFE calculations mainly based on LOMAP with a new ROCS similarity heuristic
Long MD Simulations. Performs long MD simulations starting from the output of the Protein-Ligand or the Solvate and Run MD floes. The Long MD runs in chunks of max 10 hrs to overcome AWS parallel cube running time limitation
MD API Dataset Converter. The old openmm_orion MD pkg have been refactored in multiple pkgs (orionmdcore and oemdaffinity). As consequence a change in the API has happened. The MD API Datatset Converter floe allows to convert datasets generated from the old openmm_orion pkg version <=4.0.2 to the new API >=5.0.3
The MD floes and Analysis have now better support for Implicit Solvent Calculations
Non Equilibrium switching floes are now uploading file results
RBFECMapper cube. The mapper cube produces edges made of ligand pairs to run relative binding affinity calculations starting from a given set of ligands
RBFECMapperFloeReport. This cube is designed to work with the mapper cube output to generates the floe report for the Orion UI displaying the graph of the generated edge map network
RBFECMapperResultToFile. This cube uploads a file to Orion with the mapper cube results
MDProxyCube cube.The MD Proxy cube runs chucks of MD simulations in cycles till the desired total md running time has been reached
MDRecoveryRestartProxyCube. This cube is able to restart or recover a previously run long MD simulation and it is used as support of the MD proxy cube.
All the Protein_Ligand Analysis cubes have been improved to support Implicit Solvent
TrajToOEMolCube cube. Performance improvements and long md trajectory support. The frame stride parameter has been added to the list of parameters
v 4.0.1 June 2021¶
Non-Equilibrium Switching floes for Relative Binding Free Energy (RBFE) affinity calculations
New knowledge-based ensemble score BintScore for pose stability
Support for taking Posit multi-receptor output as input to protein-ligand MD
OpenFF 1.3.1a1 support
Non-Equilibrium Switching. Relative Binding Free energy calculations and estimate of Binding Affinity, starting from equilibrium MD calculations of the bound and unbound ligands.
Ligand Bound and Unbound Equilibration for NES. Performs the equilibrium MD calculations of the bound and unbound ligands needed for NES, starting from an input protein and a set of posed ligands.
Equilibrium and Non Equilibrium Switching. Equilibrium MD runs followed by Non-Equilibrium Switching, starting from an input protein and a set of posed ligands.
Non-Equilibrium Switching Recovery. This floe attempts to produce results from uncompleted NES runs, starting from the recovery file.
Compare Experimental Affinity with NES Results. Datasets from a completed NES run can be re-analyzed by comparison to a new set of experimental data.
Short Trajectory MD with Analysis. The Bint score analysis has been added and Posit support
Analyze Protein-Ligand MD. The Bint score analysis has been added
Cofactors have been added to the MMPBSA score calculations
BoundUnboundSwitching cube. This cube accept a flask and emit on the bound port the flask containing the a complex while the unbound flask is emitted on the standard output port
RBFECEdgeGathering cube. This cube gathers the MD equilibrium simulation data related to the Bound and Unbound simulations and creates edges used to perform relative binding affinity calculations
NESGMXChimera cube. This cube generates a chimera molecule and injecting it on select frames from the Bound and Unbound simulations for the Gromacs forward and reverse Non-Equilibrium simulations
NESGMX cube.This cubes runs the forward and reverse Bound and Unbound starting equilibrium frames by using Gromacs
NESAnalysis cube. This cube collects the data generated from the Non-Equilibrium runs and calculates the relative binding affinities
PlotNESResults cube. This cube generates plots for the Relative binding affinities and the estimated Absolute Affinities versus the provided experimental data. Relevant statistics are calculated and tabled
PredictDGFromDDG cube. This cube applies the Maximum likelihood Estimator method to predict the absolute binding affinities starting from the relative binding affinities
BintScoreInitialPoseAndTrajectory cube. This cube calculates a trajectory ensemble BintScore relative to an initial pose.
Complex Preparation Cube. This cube has been updated to give better support for clashes detected between the ligands and the other flask components for Posit support
v2.0.0 September 2020¶
Ligand centric cluster Analysis
New Parametrization Engine
OpenFF 1.2.0 (Parsley) support
Solvate and Run Protein-Ligand MD. Runs MD on a Protein-Ligand system
Analyze Protein-Ligand MD. Performs Energetic and Clustering Analysis on the output produced by the
Solvate and Run Protein-Ligand MDfloe
Extract Short Trajectory MD results for Download. Extract the results produced by the
Short Trajectory MD with Analysisfloe as file to download
A new Equilibration IV stage has been added to the Short Trajectory MD floe
MD Componentscube has been added to support the new Parametrization Engine
Support for OpenFF 1.1.0 (Parsley), the March 2020 release from the Open Force Field Initiative
Support for Cuda 10.0
Exposed a new parameter in the
TrajToOEMol Cubeto set the water cutoff distance. This distance is used to select water molecules around the protein-ligand binding site for each trajectory frame and producing a multi conformer water molecule
New default parameters have been set on the STMDA floe
Support for the two force fields from the Open Force Field Initiative: Smirnof99Frosst and OpenFF 1.0.0 (parsley)
A new automatic color style is applied to the clustering in the
Short trajectory MD analysisto match the cluster colors in the Floe Report
Fixed a wrong setting in the
Solvation Cubethat was placing solvent molecules too close to the solute. This could have produced un-realistic results for some systems where water molecules could have been placed inside proteins
Fixed a bug in the GAFF/GAFF2 force field where 1-4 interactions were not correctly scaled
Fixed a bug related to un-wanted ligand atom re-ordering
Fixed a bug in the protein-ligand active site depiction
A new Plain Gromacs floe has been added to perform MD by using Gromacs .tpr files
The Yank solvation free energy floe has been removed
The force field parametrization cube now support open force field 1.0.0 (parsley)
The trajectory to multi conformer cube is now adding to the record protein-ligand binding site close waters. These are used to perform MMPBSA calculations with explicit water
Upgrades to the trajectory analysis in floe
Short Trajectory MD with Analysisexpose key results to the Analyze page and 3D visualization page in Orion.
Fixed bug in setting restraints in GROMACS cubes.
Fixed bug in ordering results in the floe report in floe
Short Trajectory MD with Analysis.
The MD Spruce Prep Floe has been removed. Proteins must be prepared with the Spruce Prep floes available in the Classic floes now.
The calculation of MMPBSA can now be also performed by using explicit waters (still experimental)
The MD Spruce Prep Floe has been removed
The Simple MD Floe has been renamed the Plain MD Floe
A new cube has been developed to check the record size before writing to the Orion backend to avoiding floe failures. The new cube has been added to all the floes for sanity check.
A new cube to estimate the water number around a ligand-protein complex has been developed. The cube is used in the MMPBSA calculation with the explicit water flag set on
Exposed MMPBSA ensemble average and standard deviation in the Trajectory Poisson-Boltzmann and Surface Area Energies so that it can be displayed in the Analyze page in Orion.
Generate Ligand Floe Report HTML from Protein-Ligand MD Traj Analysis. now generates trajectory average and median molecules for protein and ligand, with one conformer for each major cluster. These are exposed int the 3D visualization page in Orion.
Cluster Ligand Traj OEMol now exposes a link to the per-ligand floe report page so it is available in the Analyze page in Orion.
In Complex Preparation traditional references to the full periodic supermolecular ensemble as a “system” have been replaced with references to a “flask” by analogy with an assay well.
In MDFloeReportCube the floe report now generates tiled links to individual ligands in the same order as the initial list of ligands.
In MDFloeReportCube the floe report tiles now show how many major clusters were found for each ligand.
Hint interactions and Styles have been removed from receptors and ligands in the Protein, Ligand and FF parametrization setting cubes that could cause problems along the MD analysis stages (debugging is in progress)
A bug has been fixed in the ligand Elf10 charging cube that was causing problems when carboxylic acid was present in a ligand to be charged
The Trajectory to OEMol, Interaction Energies and PBSA calculation cubes have been updated to account for the explicit water in the new MMPBSA calculation