Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?

Liu, Shuai; Wang, Lingle; Mobley, David L.

doi:10.1021/acs.jcim.5b00057

Cited by 46 publications

(82 citation statements)

References 22 publications

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“…Glycine mutations, which were considered in the FEP studies, require the ability to change the charge on the C α atom and to scale CMAP interactions by λ , which are not currently implemented in the CHARMM molecular dynamics package. Proline mutations are even more challenging, requiring topology changes via the opening of a ring . Such mutations could be allowed through the use of soft bonds and other advances.…”

Section: Discussionmentioning

confidence: 99%

Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme

2018

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The estimation of changes in free energy upon mutation is central to the problem of protein design. Modern protein design methods have had remarkable success over a wide range of design targets, but are reaching their limits in ligand binding and enzyme design due to insufficient accuracy in mutational free energies. Alchemical free energy calculations have the potential to supplement modern design methods through more accurate molecular dynamics based prediction of free energy changes, but suffer from high computational cost. Multisite λ dynamics (MSλD) is a particularly efficient and scalable free energy method with potential to explore combinatorially large sequence spaces inaccessible with other free energy methods. This work aims to quantify the accuracy of MSλD and demonstrate its scalability. We apply MSλD to the classic problem of calculating folding free energies in T4 lysozyme, a system with a wealth of experimental measurements. Single site mutants considering 32 mutations show remarkable agreement with experiment with a Pearson correlation of 0.914 and mean unsigned error of 1.19 kcal/mol. Multisite mutants in systems with up to five concurrent mutations spanning 240 different sequences show comparable agreement with experiment. These results demonstrate the promise of MSλD in exploring large sequence spaces for protein design.

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Section: Discussionmentioning

confidence: 99%

Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme

2018

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“…The only current limit is that rings are required to be preserved. 40 With this strategy, a single topology description is achieved: any atom that does not match is made a dummy atom. FESetup allows equilibration of the solvated simulation systems and ensures that "forward" and "backward" simulations have the same number of total atoms.…”

Section: Rafe Setupmentioning

confidence: 99%

Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages

Loeffler

Bosisio

Matos

et al. 2018

J. Chem. Theory Comput.

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125

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Alchemical free energy calculations are an increasingly important modern simulation technique to calculate free energy changes on binding or solvation. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS, and SOMD include support for the method. Implementation details vary among those codes, but users expect reliability and reproducibility, i.e., for a given molecular model and set of force field parameters, comparable free energy differences should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy (RAFE) simulation is increasingly used to support molecule discovery projects, yet the reproducibility of the methodology has been less well tested than its absolute counterpart. Here we present RAFE calculations of hydration free energies for a set of small organic molecules and demonstrate that free energies can be reproduced to within about 0.2 kcal/mol with the aforementioned codes. Absolute alchemical free energy simulations have been carried out as a reference. Achieving this level of reproducibility requires considerable attention to detail and package-specific simulation protocols, and no universally applicable protocol emerges. The benchmarks and protocols reported here should be useful for the community to validate new and future versions of software for free energy calculations.

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“…Another potential source of problems is the alchemical perturbation itself: transformations between chemically very different ligands can make the simulations hard to converge, leading to longer, and thus more costly, simulations . This can be especially problematic in scaffold‐hopping modifications, when rings are closed or their size is changed in single‐topology approaches . However, this is not the case for dual‐topology approaches, and there has been significant progress to alleviate that problem in single‐topology approaches recently .…”

Section: Introductionmentioning

confidence: 99%

“…[5] This can be especially problematic in scaffold-hopping modifications, [6][7][8][9] when rings are closed or their size is changed in single-topology approaches. [10,11] However,t his is not the case for dual-topology approaches, [12] and there has been significant progress to alleviate that problem in single-topology approaches recently. [13] Finally,t he creation and annihilation of charges in an alchemical transformation is al ong-standing problem that has not been solved completely.…”

Section: Introductionmentioning

confidence: 99%

Towards full Quantum‐Mechanics‐based Protein–Ligand Binding Affinities

2017

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Computational methods play a key role in modern drug design in the pharmaceutical industry but are mostly based on force fields, which are limited in accuracy when describing non-classical binding effects, proton transfer, or metal coordination. Here, we propose a general fully quantum mechanical (QM) scheme for the computation of protein-ligand affinities. It works on a single protein cutout (of about 1000 atoms) and evaluates all contributions (interaction energy, solvation, thermostatistical) to absolute binding free energy on the highest feasible QM level. The methodology is tested on two different protein targets: activated serine protease factor X (FXa) and tyrosine-protein kinase 2 (TYK2). We demonstrate that the geometry of the model systems can be efficiently energy-minimized by using general purpose graphics processing units, resulting in structures that are close to the co-crystallized protein-ligand structures. Our best calculations at a hybrid DFT level (PBEh-3c composite method) for the FXa ligand set result in an overall mean absolute deviation as low as 2.1 kcal mol . Though very encouraging, an analysis of outliers indicates that the structure optimization level, conformational sampling, and solvation treatment require further improvement.

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Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?

Cited by 46 publications

References 22 publications

Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme

Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme

Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages

Towards full Quantum‐Mechanics‐based Protein–Ligand Binding Affinities

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