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Large scale affinity calculations of cyclodextrin host-guest complexes: Understanding the role of reorganization in the molecular recognition process.

ABSTRACT: Host-guest inclusion complexes are useful models for understanding the structural and energetic aspects of molecular recognition. Due to their small size relative to much larger protein-ligand complexes, converged results can be obtained rapidly for these systems thus offering the opportunity to more reliably study fundamental aspects of the thermodynamics of binding. In this work, we have performed a large scale binding affinity survey of 57 ?-cyclodextrin (CD) host guest systems using the binding energy distribution analysis method (BEDAM) with implicit solvation (OPLS-AA/AGBNP2). Converged estimates of the standard binding free energies are obtained for these systems by employing techniques such as parallel Hamitionian replica exchange molecular dynamics, conformational reservoirs and multistate free energy estimators. Good agreement with experimental measurements is obtained in terms of both numerical accuracy and affinity rankings. Overall, average effective binding energies reproduce affinity rank ordering better than the calculated binding affinities, even though calculated binding free energies, which account for effects such as conformational strain and entropy loss upon binding, provide lower root mean square errors when compared to measurements. Interestingly, we find that binding free energies are superior rank order predictors for a large subset containing the most flexible guests. The results indicate that, while challenging, accurate modeling of reorganization effects can lead to ligand design models of superior predictive power for rank ordering relative to models based only on ligand-receptor interaction energies.

SUBMITTER: Wickstrom L

PROVIDER: S-EPMC4137772 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Project description:Understanding the fine balance between changes of entropy and enthalpy and the competition between a guest and water molecules in molecular binding is crucial in fundamental studies and practical applications. Experiments provide measurements. However, illustrating the binding/unbinding processes gives a complete picture of molecular recognition not directly available from experiments, and computational methods bridge the gaps. Here, we investigated guest association/dissociation with β-cyclodextrin (β-CD) by using microsecond-time-scale molecular dynamics (MD) simulations, postanalysis and numerical calculations. We computed association and dissociation rate constants, enthalpy, and solvent and solute entropy of binding. All the computed values of kon, koff, ΔH, ΔS, and ΔG using GAFF-CD and q4MD-CD force fields for β-CD could be compared with experimental data directly and agreed reasonably with experiment findings. In addition, our study further interprets experiments. Both force fields resulted in similar computed ΔG from independently computed kinetics rates, ΔG = -RT ln(kon·C0/koff), and thermodynamics properties, ΔG = ΔH - TΔS. The water entropy calculations show that the entropy gain of desolvating water molecules are a major driving force, and both force fields have the same strength of nonpolar attractions between solutes and β-CD as well. Water molecules play a crucial role in guest binding to β-CD. However, collective water/β-CD motions could contribute to different computed kon and ΔH values by different force fields, mainly because the parameters of β-CD provide different motions of β-CD, hydrogen-bond networks of water molecules in the cavity of free β-CD, and strength of desolvation penalty. As a result, q4MD-CD suggests that guest binding is mostly driven by enthalpy, while GAFF-CD shows that gaining entropy is the major driving force of binding. The study deepens our understanding of ligand-receptor recognition and suggests strategies for force field parametrization for accurately modeling molecular systems.

Project description:Computational prediction of noncovalent binding free energies with methods based on molecular mechanical force fields has become increasingly routine in drug discovery projects, where they promise to speed the discovery of small molecule ligands to bind targeted proteins with high affinity. Because the reliability of free energy methods still has significant room for improvement, new force fields, or modifications of existing ones, are regularly introduced with the aim of improving the accuracy of molecular simulations. However, comparatively little work has been done to systematically assess how well force fields perform, particularly in relation to the calculation of binding affinities. Hardware advances have made these calculations feasible, but comprehensive force field assessments for protein-ligand sized systems still remain costly. Here, we turn to cyclodextrin host-guest systems, which feature many hallmarks of protein-ligand binding interactions but are generally much more tractable due to their small size. We present absolute binding free energy and enthalpy calculations, using the attach-pull-release (APR) approach, on a set of 43 cyclodextrin-guest pairs for which experimental ITC data are available. The test set comprises both α- and β-cyclodextrin hosts binding a series of small organic guests, each with one of three functional groups: ammonium, alcohol, or carboxylate. Four water models are considered (TIP3P, TIP4Pew, SPC/E, and OPC), along with two partial charge assignment procedures (RESP and AM1-BCC) and two cyclodextrin host force fields. The results suggest a complex set of considerations when choosing a force field for biomolecular simulations. For example, some force field combinations clearly outperform others at the binding enthalpy calculations but not for the binding free energy. Additionally, a force field combination which we expected to be the worst performer gave the most accurate binding free energies - but the least accurate binding enthalpies. The results have implications for the development of improved force fields, and we propose this test set, and potential future elaborations of it, as a powerful validation suite to evaluate new force fields and help guide future force field development.

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Large scale affinity calculations of cyclodextrin host-guest complexes: Understanding the role of reorganization in the molecular recognition process.

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