April Product Updates: Announcing F-SAPT, a Workflow for Understanding Molecular Interactions

We are pleased to announce the release of a major new workflow, F-SAPT (Functional group symmetry-adapted perturbation theory): a quantum mechanical method for exploring the underlying driving forces for noncovalent, intermolecular interactions between molecules (e.g., a ligand and a protein) and to better understand how to optimize the molecules to tune the interaction. 

By helping to explain how molecules interact using quantum mechanics, F-SAPT can provide deeper insights to inform molecule design. F-SAPT can be complementary to classical methods such as Free Energy Perturbation (FEP) by providing a structure-based explanation for why a specific trend exists in predicted and/or experimental values.

F-SAPT

F-SAPT is a quantum chemistry method to compute and analyze noncovalent, intermolecular interactions between molecular systems. F-SAPT is an extension of SAPT (symmetry-adapted perturbation theory) and, depending on the configuration, includes the ability to only perform a SAPT calculation. To understand how F-SAPT can be used, it is important to first understand SAPT.

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SAPT calculates the total interaction energy between two interacting molecular systems (termed monomers). In drug discovery, these interacting systems could be a ligand and a protein. The monomers are not restricted to be single molecules, so one monomer might include a protein, associated water molecules, bound ions, and any other chemical species present. The interaction energy is computed between the two systems in terms of physically-meaningful energy components: electrostatics, exchange-repulsion, dispersion, and induction. The total interaction energy is the sum of these energy components.

SAPT can also be applied to calculate the total interaction energy for other applications, such as between carbon dioxide and a metal–organic framework (MOF) in carbon capture or a reactant (substrate) and catalyst in a chemical synthesis.

F-SAPT provides a decomposition of these energy components into the pairwise interactions between user-defined sub-structures (termed fragments) of each molecular system. The ability to examine these pairwise interactions allows greater insight into what specific atoms are driving the attractive and/or repulsive interactions between the two systems. 

In the case of a ligand and a protein with the surrounding environment, the ligand can be fragmented into different functional groups, the protein into individual side chains and peptide bonds, and the surrounding environment into individual water molecules and ions. 

These methods provide users with the ability to explore the underlying driving forces for noncovalent, intermolecular interactions and to better understand how to further optimize the involved molecules.

Automatic Protein Fragmentation

Fragmenting a protein and surrounding environment and preparing the system for an F-SAPT calculation can be a tedious process, given the large number of residues present and the labor-intensive, error-prone procedure of creating a cut-out of the binding site. To streamline this step, Promethium offers the ability to automatically fragment residues and prepare the protein and surrounding environment according to a set of user-configurable parameters such as specific residues to include and a cut-out of the binding site based on distance from the ligand or a target number of atoms in the prepared system. The cut-out functionality also includes capping of residues to terminate protein chains without introducing incorrect dipole moments. 

F-SAPT Energy Differences Analysis

F-SAPT is often used to quantitatively compare the effects of functional group substitutions on interactions between a ligand and protein. To simplify creating that comparison, Promethium includes an analysis tool that allows users to quickly compare the interaction energy difference between two similar F-SAPT calculations. This analysis tool extends the usability of F-SAPT in molecular design and can help explain differences in binding energy that arise from substitutions in the ligand structure.

Industry Applications of F-SAPT

‍Understand preferential binding of different small molecules: As demonstrated by published research from Bristol Myers Squibb and Georgia Institute of Technology, F-SAPT has been successfully utilized to investigate the driving forces in the small molecule inhibition of factor Xa, a key enzyme involved in blood coagulation and the target for anticoagulation drugs used to prevent stroke in high-risk patients. F-SAPT provides a compelling explanation that intermediate-ranged electrostatic interactions are a key driver for the experimentally-observed preferential binding of ligands that contain aromatic chloride over methyl aryl substituted ligands (https://doi.org/10.1002/chem.201701031). 

Design better lead compounds: Silicon Therapeutics has also described how F-SAPT was used in the lead optimization stage in the development of their clinical-phase oncology molecule, SNX281. In conjunction with Relative Binding Free Energy (RBFE) Calculations and Active Learning, F-SAPT was used to prioritize molecules for synthesis and evaluation in experimental binding assays; a correlation between F-SAPT predicted interaction energy and experimental IC50 was noted, and the use of F-SAPT resulted in better ranking of candidate molecules than RBFE alone (https://doi.org/10.1101/2022.05.23.493001). 

The F-SAPT workflow is now available in Promethium through the Graphical UI and the API. Please reach out to our team via promethium@qcware.com with any questions!