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1. 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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2. 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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3. 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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4. 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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5. Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations

   https://doi.org/10.1021/acs.jctc.2c01258  

   Hsu, Wei-Tse; Piomponi, Valerio; Merz, Pascal T.; Bussi, Giovanni; Shirts, Michael R. (March 2023, Journal of Chemical Theory and Computation)

   Performing alchemical transformations, in which one molecular system is nonphysically changed to another system, is a popular approach adopted in performing free energy calculations associated with various biophysical processes, such as protein–ligand binding or the transfer of a molecule between environments. While the sampling of alchemical intermediate states in either parallel (e.g., Hamiltonian replica exchange) or serial manner (e.g., expanded ensemble) can bridge the high-probability regions in the configurational space between two end states of interest, alchemical methods can fail in scenarios where the most important slow degrees of freedom in the configurational space are, in large part, orthogonal to the alchemical variable, or if the system gets trapped in a deep basin extending in both the configurational and alchemical space. To alleviate these issues, we propose to use alchemical variables as an additional dimension in metadynamics, making it possible to both sample collective variables and to enhance sampling in free energy calculations simultaneously. In this study, we validate our implementation of “alchemical metadynamics” in PLUMED with test systems and alchemical processes with varying complexities and dimensionalities of collective variable space, including the interconversion between the torsional metastable states of a toy system and the methylation of a nucleoside both in the isolated form and in a duplex. We show that multidimensional alchemical metadynamics can address the challenges mentioned above and further accelerate sampling by introducing configurational collective variables. The method can trivially be combined with other metadynamics-based algorithms implemented in PLUMED. The necessary PLUMED code changes have already been released for general use in PLUMED 2.8. 

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