Cresset Flare 2024 v9.0 brings new and enhanced scientific features and methods for all users. These include Homology Modeling to create reliable 3D models for protein targets for which crystallographic information is not available, ensemble Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) on dynamics trajectories for estimating binding free energy, a full integration of Spark in Flare, and enhanced protein preparation.
Cresset Flare 2024 v9.0 Tested Picture
In this release, we have also further expanded and enhanced the choice of visual tools to investigate the results of Flare FEP experiments and analyze dynamics trajectories, and added many new options for fine-tuning the experiments.
Furthermore, the enhanced Extension Manager provides a streamlined workflow for the installation of Flare Python Extensions.
Create reliable 3D structures for your protein targets with Homology Modeling
Experimental information about the 3D protein structure may not be available for many interesting biological targets, for example, many GPCRs, ion channels and novel targets. In all these cases, Homology Modeling can be used to create a reliable 3D structure to use in structure-based studies, from docking and scoring to molecular dynamics.
Homology Modeling in Flare uses the robust ProMod31 algorithm, deployed on a secure server hosted by Cresset. This enables Flare to build reliable homology models in just a few minutes, starting from aligned target sequences and template chains with sequence identity as low as 30%.
Estimate the binding free energy for your ligands with MM/GBSA on dynamics trajectories
MM/GBSA2 is a popular method to estimate the binding free energy for ligand-protein complexes, providing a good balance between accuracy of predictions and computational efficiency.
Building on the implementation of the method in Flare V8, this latest release expands the MM/GBSA capabilities of Flare to include the option to run the calculations on an ensemble of conformations from a molecular dynamics experiment. MM/GBSA Dynamics in Flare allows you to score multiple ligand-protein ensembles at a time, choosing from a choice of different implicit solvents, and selecting the desired trajectory range and score interval .
Flare V9 features a full integration of Spark, Cresset’s best-in-class bioisostere application.4 This is the result of a two-year project, during which we have worked hard to give Spark users access to the variety of methods and features which Flare provides for preparing Spark experiments and optimizing results, at the same time carefully preserving the ease of use of Spark. Using Spark in Flare offers several advantages, giving you access to:
- Accurate preparation of the experiment (starter ligand, water, receptor protein), particularly useful for advanced experiments such as ligand growing and joining, water replacement, growing with docking
- A wide range of methods for refinement and post-processing, including docking and scoring, Cresset’s patented ligand-based alignment, Electrostatic Complementarity™, MM/GBSA, Flare FEP
- A fully fledged API, as part of the Flare Python API
- Full synergy between ligand-based and structure-based approaches
Spark provides access to an outstanding collection of millions of bioisosteres to generate new project ideas. In the enhanced ‘Database selection & Advanced options’ panel (Figure 7) you can select the databases you wish to search, set an experiment name and a role for the results, and choose whether to remove duplicate results from different Spark experiments.
One of the many advantages of running Spark experiments in Flare is that you are no longer limited to one starter molecule, one protein, one set of results (in practice, one Spark experiment) per project. Flare enables you to run multiple different experiments and keep the results nicely organized in different roles within the same Flare project.
Furthermore, all Spark features are now accessible from the Flare Python API. This makes it easy to set up custom workflows (for example, run a Spark search and automatically re-dock results, or automatically score them with MM/GBSA). Command-line scripts are also available as a drop-in replacement for existing Spark command-line tools.
New science features and analysis tools for enhanced molecular dynamics experiments
Several new features and analysis tools for molecular dynamics are available in this release. Below we will highlight some of the most important new additions.
We have added the Principal Component Analysis (PCA) plot (Figure 8) to the wide and growing choice of analysis tools which help Flare users analyze and understand Dynamics results. You can use this visual tool to monitor the most important motions of your biomolecule over the Dynamics trajectory.
Starting from the coordinates of each heavy atom along the trajectory, the method follows the protein dynamics along its Principal Components (PCs), representing the directions of greatest variance in the data, with the first few PCs capturing the most significant modes of motion in the system.
We have also added several new advanced options which you can use to fine-tune your experiments. For example, you can now create, use and save bespoke equilibration protocols, by adding/removing existing steps from the ‘Standard’ protocol, and by changing the conditions for performing each step.
We have also added several additional lipid membrane models for performing molecular dynamics on membrane proteins, and added the possibility to select the explicit water model to use with each model.
Finally, among many other new nice features, you can now:
- Set positional constraints to protein atoms (in addition to distance constraints) to restrain protein movements
- Run simulations on ligands only
New and enhanced features for Flare FEP
Flare FEP includes several new and enhanced features in Flare V9, with some of the most interesting changes summarized below.
An enhanced Activity Plot enables you to monitor the precision of the FEP calculation, expressed as the proportion of the predicted active molecules which are indeed experimentally active. The desired activity threshold for separating active/inactive molecules can be set using the slider at the top of the graph . Furthermore, in Flare V9 you can change the activity unit for drawing the plot, switching from the default ΔG to µM or nM activity.
The new graph error analysis is an additional tool which helps you to troubleshoot FEP results, by color-coding all the calculated links in the perturbation network based on the contribution they make to the overall calculation error . This facilitates quick and easy identification of problematic links which have a detrimental effect on the precision of the Flare FEP calculation.
Finally, the ‘Start’ button now offers the option to recalculate only the ΔΔGs when calculations are complete (useful for example when molecules are removed from the perturbation network).
Enhanced preparation of biomolecular system for further studies
In this release of Flare, we have introduced new options to the ‘Protein Preparation’ dialog, to make the preparation of the biomolecular system under study more flexible and comprehensive.
New options are available to:
- Remove several types of post-translational modifications
- Control changes in protonation and tautomeric state for protein residues and/or ligand and cofactors
- Enable/disable Asn/Gln/His flips
- Modify only selected residues
Streamlined installation of Flare Python Extensions
An enhanced Extension Manager enables the seamless installation and update of Cresset or customer-created Python extensions with minimal user intervention. Extension packages can be installed manually by end users, or programmatically by IT, and it is possible to decide whether to update the extensions manually or automatically, whenever a new or updated extension package is available.
Find the files you want to open more quickly
In Flare V9 we have implemented a time-saving usability improvement to help you quickly navigate to recent files and folders. The File menu shows, in addition to the list of recent projects, a list of files you can select with a click (Figure 16) to easily re-open them, and frequently visited places to navigate to.
A wealth of enhancements and improvements
At every release of Flare, we work very hard at implementing not only additional interesting science, but as many as possible usability enhancements, many of which are in direct response to feedback from our users. Some other interesting new features are listed below:
- If you enjoy working with the Flare Python API, in Flare V9 you can launch and configure a JupyterLab Notebook to use a Flare python kernel which enables the Notebook to interact and work with Flare
- Additional conformation sampling for flexible rings when docking in ‘Accurate’ mode
- For docked poses generated in the presence of flickering waters, the new ‘Flickering waters’ column captures whether the pose was created with each flickering water switched either ON or OFF
- Add water molecules in the desired 3D position with the new ‘Add Water’ button in the Editing tools
- Merge two or more selected ligands into a single molecule with the new ‘Merge Ligands’ button in the Ligand tab (in preparation, for example, to a ‘Join Two Ligands’ Spark experiment)
- Color your protein residues by sequence identity or similarity towards a target protein
- Tag protein residues
- Enhancements to the Ligands table include counts of number of H-bond acceptors/donors for each molecule, custom heatmaps to color-code columns according to a user-defined sets of rules, collapse or expand all roles (also available for the Proteins table), and editable cells in the ‘Tag’ column, enabling to quickly set text or numerical tags which can be used for filtering ligands
- New functions in the Sequences tab include Tags for protein residues, and a new option to sequence-align only picked protein chains
- New and enhanced scripts for pyflare users
