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1. Performance and Analysis of the Alchemical Transfer Method for Binding Free Energy Predictions of Diverse Ligands

   Chen Lieyang; Wu, Yujie; Wu, Chuanjie; Silveira, Ana; Sherman, Woody; Xu, Huafeng; Gallicchio, Emilio (August 2023, arXivorg)

   The Alchemical Transfer Method (ATM) is herein validated against the relative binding free energies of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM software to compute the relative binding free energies (RBFE) of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations. The novel coordinate perturbation scheme and a dual-topology approach of ATM address some of the challenges of single-topology alchemical relative binding free energy methods. Specifically, ATM eliminates the need for splitting electrostatic and Lennard-Jones interactions, atom mapping, defining ligand regions, and post-corrections for charge-changing perturbations. Thus, ATM is simpler and more broadly applicable than conventional alchemical methods, especially for scaffold-hopping and charge-changing transformations. Here, we performed well over 500 relative binding free energy calculations for eight protein targets and found that ATM achieves accuracy comparable to existing state-of-the-art methods, albeit with larger statistical fluctuations. We discuss insights into specific strengths and weaknesses of the ATM method that will inform future deployments. This study confirms that ATM is applicable as a production tool for relative binding free energy (RBFE) predictions across a wide range of perturbation types within a unified, open-source framework. 

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2. To probe the binding pathway of a selective compound (D089-0563) to c-MYC Pu24 G-quadruplex using free ligand binding simulations and Markov state model analysis

   https://doi.org/10.1039/d0cp03863f  

   Chen, Brian; Fountain, Griffin; Sullivan, Holli-Joi; Paradis, Nicholas; Wu, Chun (October 2020, Physical Chemistry Chemical Physics)

   null (Ed.)

   D089-0563 is a highly promising anti-cancer compound that selectively binds the transcription-silencing G-quadruplex element (Pu27) at the promoter region of the human c-MYC oncogene; however, its binding mechanism remains elusive. The structure of Pu27 is not available due to its polymorphism, but the G-quadruplex structures of its two shorter derivatives in complex with a ligand (Pu24/Phen-DC3 and Pu22/DC-34) are available and show significant structural variance as well as different ligand binding patterns in the 3′ region. Because D089-0563 shares the same scaffold as DC34 while having a significantly different scaffold from Phen-DC3, we picked Pu24 instead of Pu22 for this study in order to gain additional ligand binding insight. Using free ligand molecular dynamics binding simulations (33 μs), we probed the binding of D089-0563 to Pu24. Our clustering analysis identified three binding modes (top, side, and bottom) and subsequent MMPBSA binding energy analysis identified the top mode as the most thermodynamically stable. Our Markov State Model (MSM) analysis revealed that there are three parallel pathways for D089-0563 to the top mode from unbound state and that the ligand binding follows the conformational selection mechanism. Combining our predicted complex structures with the two experimental structures, it is evident that structural differences in the 3′ region between Pu24 and Pu22 lead to different binding behaviors despite having similar ligands; this also explains the different promoter activity caused by the two G-quadruplex sequences observed in a recent synthetic biology study. Based on interaction insights, 625 D089-0563 derivatives were designed and docked; 59 of these showed slightly improved docking scores. 

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3. Free Energy-Based Computational Methods for the Study of Protein-Peptide Binding Equilibria

   https://doi.org/10.1007/978-1-0716-1855-4_15  

   Gallicchio, Emilio (May 2021, Methods in molecular biology)

   Simonson, Thomas (Ed.)

   This chapter discusses the theory and application of physics-based free energy methods to estimate protein-peptide binding free energies. It presents a statistical mechanics formulation of molecular binding, which is then specialized in three methodologies: (i) alchemical absolute binding free energy estimation with implicit solvation, (ii) alchemical relative binding free energy estimation with explicit solvation, and (iii) potential of mean force binding free energy estimation. Case studies of protein-peptide binding application taken from the recent literature are discussed for each method. 

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4. Validation of the Alchemical Transfer Method for the Estimation of Relative Binding Affinities of Molecular Series

   https://doi.org/10.1021/acs.jcim.3c00178  

   Sabanés Zariquiey, Francesc; Pérez, Adrià; Majewski, Maciej; Gallicchio, Emilio; De Fabritiis, Gianni (April 2023, Journal of Chemical Information and Modeling)

   The accurate prediction of protein-ligand binding affinities is crucial for drug discovery. Alchemical free energy calculations have become a popular tool for this purpose. However, the accuracy and reliability of these methods can vary depending on the methodology. In this study, we evaluate the performance of a relative binding free energy protocol based on the alchemical transfer method (ATM), a novel approach based on a coordinate transformation that swaps the positions of two ligands. The results show that ATM matches the performance of more complex free energy perturbation (FEP) methods in terms of Pearson correlation, but with marginally higher mean absolute errors. This study shows that the ATM method is competitive compared to more traditional methods in speed and accuracy and offers the advantage of being applicable with any potential energy function. 

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5. Taming multiple binding poses in alchemical binding free energy prediction: the β-cyclodextrin host–guest SAMPL9 blinded challenge

   https://doi.org/10.1039/D3CP02125D  

   Khuttan, Sheenam; Azimi, Solmaz; Wu, Joe Z.; Dick, Sebastian; Wu, Chuanjie; Xu, Huafeng; Gallicchio, Emilio (September 2023, Physical Chemistry Chemical Physics)

   We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partial charge force field to the SAMPL9 bCD host-guest binding free energy prediction challenge that comprises a combination of complexes formed between five phenothiazine guests and two cyclodextrin hosts. Multiple chemical forms, competing binding poses, and computational modeling challenges pose significant obstacles to obtaining reliable computational predictions for these systems. The phenothiazine guests exist in solution as racemic mixtures of enantiomers related by nitrogen inversions that bind the hosts in various binding poses, each requiring an individual free energy analysis. Due to the large size of the guests and the conformational reorganization of the hosts, which prevent a direct absolute binding free energy route, binding free energies are obtained by a series of absolute and relative binding alchemical steps for each chemical species in each binding pose. Metadynamics-accelerated conformational sampling was found to be necessary to address the poor convergence of some numerical estimates affected by conformational trapping. Despite these challenges, our blinded predictions quantitatively reproduced the experimental affinities for the beta-cyclodextrin host and, to a lesser extent, those with a methylated derivative. The work illustrates the challenges of obtaining reliable free energy data in in-silico drug design for even seemingly simple systems and introduces some of the technologies available to tackle them. 

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