We introduce the self-Relative Binding Free Energy (self-RBFE) approach to evaluate the intrinsic statistical variance of dual-topology alchemical binding free energy estimators. The self-RBFE is the relative binding free energy between a ligand and a copy of the same ligand, and its true value is zero. Nevertheless, because the two copies of the ligand move independently, the self-RBFE value produced by a finite-length simulation fluctuates and can be used to measure the variance of the model. The results of this validation provide evidence that a significant fraction of the errors observed in benchmark studies reflect the statistical fluctuations of unconverged estimates rather than the models' accuracy. Furthermore, we find that ligand reorganization is a significant contributing factor to the statistical variance of binding free energy estimates and that metadynamics-accelerated conformational sampling of torsional degrees of freedom of the ligand can drastically reduce the time to convergence.
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Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations
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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- Award ID(s):
- 1835720
- PAR ID:
- 10502645
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Journal of Chemical Theory and Computation
- Volume:
- 19
- Issue:
- 6
- ISSN:
- 1549-9618
- Page Range / eLocation ID:
- 1805 to 1817
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acs.jctc.2c01258
