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Predicting Binding Free Energies: Frontiers and Benchmarks.

ABSTRACT: Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions among its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early-stage drug discovery. However, many hurdles remain in making them a robust and reliable tool. In this review, we highlight key challenges of these calculations, discuss some examples of these challenges, and call for the designation of standard community benchmark test systems that will help the research community generate and evaluate progress. In our view, progress will require careful assessment and evaluation of new methods, force fields, and modeling innovations on well-characterized benchmark systems, and we lay out our vision for how this can be achieved.

SUBMITTER: Mobley DL

PROVIDER: S-EPMC5544526 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Predicting Binding Free Energies: Frontiers and Benchmarks.

Mobley David L DL Gilson Michael K MK

Annual review of biophysics 20170407

Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions among its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in e ...[more]

PMID: 28399632

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Project description:One of the long-standing holy grails of molecular evolution has been the ability to predict an organism's fitness directly from its genotype. With such predictive abilities in hand, researchers would be able to more accurately forecast how organisms will evolve and how proteins with novel functions could be engineered, leading to revolutionary advances in medicine and biotechnology. In this work, we assemble the largest reported set of experimental TEM-1 β-lactamase folding free energies and use this data in conjunction with previously acquired fitness data and computational free energy predictions to determine how much of the fitness of β-lactamase can be directly predicted by thermodynamic folding and binding free energies. We focus upon β-lactamase because of its long history as a model enzyme and its central role in antibiotic resistance. Based upon a set of 21 β-lactamase single and double mutants expressly designed to influence protein folding, we first demonstrate that modeling software designed to compute folding free energies such as FoldX and PyRosetta can meaningfully, although not perfectly, predict the experimental folding free energies of single mutants. Interestingly, while these techniques also yield sensible double mutant free energies, we show that they do so for the wrong physical reasons. We then go on to assess how well both experimental and computational folding free energies explain single mutant fitness. We find that folding free energies account for, at most, 24% of the variance in β-lactamase fitness values according to linear models and, somewhat surprisingly, complementing folding free energies with computationally-predicted binding free energies of residues near the active site only increases the folding-only figure by a few percent. This strongly suggests that the majority of β-lactamase's fitness is controlled by factors other than free energies. Overall, our results shed a bright light on to what extent the community is justified in using thermodynamic measures to infer protein fitness as well as how applicable modern computational techniques for predicting free energies will be to the large data sets of multiply-mutated proteins forthcoming.

Dataset Information

Predicting Binding Free Energies: Frontiers and Benchmarks.

Publications

Predicting Binding Free Energies: Frontiers and Benchmarks.

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