OpenBioSim is delighted to highlight our long-standing collaboration with Cresset, a leading computational chemistry software company, that has culminated in the integration of our SOMD2 engine into Flare V12 — Cresset’s fully featured, industry-leading drug design software suite.

OpenBioSim at the Core of Flare FEP

SOMD2 is OpenBioSim’s next-generation engine for alchemical free energy perturbation calculations. Built directly on top of Sire and BioSimSpace — the two flagship open-source projects of OpenBioSim — SOMD2 inherits the interoperability, robustness, and scientific rigour that these frameworks have been engineered to provide. Sire underpins the molecular modelling layer, while BioSimSpace provides the workflow orchestration and engine-agnostic abstractions that make SOMD2 straightforward to embed within third-party software environments such as Flare.

With the release of Flare V12, SOMD2 has become the default FEP engine for relative binding free energy calculations within the Flare platform. This transition delivers approximately 20% faster simulation throughput compared to the previous engine, and when combined with the new “two-system” FEP links — where simulations start simultaneously from both end states of an alchemical transformation and propagate toward neighbouring λ windows, meeting in the middle — total wall-clock time per transformation is reduced by more than a factor of two. For reference, a typical BACE protein transformation that required around 8 hours in Flare V11 now completes in approximately 3.8 hours under comparable hardware conditions.

Advanced Capabilities: Ring Modifications, REST2, and GCMC

Beyond raw performance, this collaboration has brought several methodological advances to Flare users that represent the current state of the art in alchemical free energy methodology.

Ring-Breaking Transformations

Flare V12 introduces support for ring-breaking alchemical transformations, enabling scaffold hopping, ring-size modifications, and interconversion between cyclic and acyclic moieties within a single perturbation pathway. This is made possible through the use of a custom distance restraint within SOMD2. The result is that medicinal chemists can now explore significantly more diverse regions of chemical space within a single FEP campaign, without the need to decompose complex structural changes into multiple sequential transformations.

Replica Exchange with Solute Tempering (REST2)

To address convergence challenges in flexible and conformationally complex systems, Flare V12 exposes both Hamiltonian Replica Exchange and Replica Exchange with Solute Tempering (REST2) through SOMD2. REST2 introduces an effective temperature dimension by selectively heating the alchemical region of the molecule, enabling enhanced conformational sampling that would not be accessible at ambient temperature. Both methods improve overlap between neighbouring λ windows and yield more reliable free energy estimates for challenging drug-like systems.

GCMC Water Sampling via Loch

Accurate modelling of solvent effects — particularly in buried or occluded binding sites — is critical for reliable FEP predictions. To address this, SOMD2 integrates loch, OpenBioSim’s new CUDA-accelerated Grand Canonical Monte Carlo (GCMC) water sampling engine, also built on Sire and BioSimSpace. Loch enables insertion and deletion of water molecules during MD simulation, ensuring that the solvent environment around the binding site is realistically equilibrated throughout the alchemical pathway. A custom CUDA kernel parallelises thousands of GCMC trial moves simultaneously, while an approximate reaction field potential for trial evaluations — followed by a PME correction step for accepted moves — keeps overheads modest. The integration of loch into SOMD2 is now available through Flare V12’s GCMC water sampling option, providing Flare users with access to GPU-accelerated explicit solvent equilibration that is otherwise available only through specialist simulation pipelines.

Bringing Cutting-Edge Open-Source Science to Thousands of Drug Discovery Scientists

Cresset distributes Flare to thousands of drug discovery scientists worldwide through its global network of partners and licensees. The integration of SOMD2 into Flare means that this community — spanning pharmaceutical companies, biotechnology firms, and academic institutions — now has direct, seamless access to the cutting-edge open-source molecular simulation methods developed within the OpenBioSim ecosystem. For many of these users, SOMD2, Sire, and BioSimSpace represent capabilities that would otherwise require significant in-house software expertise to deploy. The Flare integration lowers that barrier entirely, embedding these tools within a polished, production-ready drug design interface. At the same time, the source code of the core molecular simulation engine is available to all, allowing scientists to verify claims made about the underlying scientific methodologies used to predict protein-ligand binding free energies.

This is precisely the model OpenBioSim was established to pursue: developing rigorous, trustworthy open-source scientific software and building the partnerships that carry it into real-world drug discovery workflows.

Outlook

The collaboration between OpenBioSim and Cresset continues to evolve. We look forward to sharing further developments as SOMD2, Sire, and BioSimSpace continue to mature and as new methodological capabilities — including absolute binding free energy protocols and enhanced sampling methods — are brought within reach of an ever broader community of computational and medicinal chemists.

Drafted by Claude and edited by Julien Michel