Interplay between Conformational Entropy and Solvation Entropy in Protein–Ligand Binding (original) (raw)
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Journal of the American Chemical Society, 2010
Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. 15 N and 2 H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.
Estimation of Conformational Entropy in Protein–Ligand Interactions: A Computational Perspective
Methods in Molecular Biology, 2011
Conformational entropy is an important component of the change in free energy upon binding of a ligand to its target protein. As a consequence, development of computational techniques for reliable estimation of conformational entropies is currently receiving an increased level of attention in the context of computational drug design. Here, we review the most commonly used techniques for conformational entropy estimation from classical molecular dynamics simulations. Although by-and-large still not directly used in practical drug design, these techniques provide a golden standard for developing other, computationally less-demanding methods for such applications, in addition to furthering our understanding of protein-ligand interactions in general. In particular, we focus here on the quasi-harmonic approximation and discuss different approaches that can be used to go beyond it, most notably, when it comes to treating anharmonic and/or correlated motions. In addition to reviewing basic theoretical formalisms, we provide a concrete set of steps required to successfully calculate conformational entropy from molecular dynamics simulations, as well as discuss a number of practical issues that may arise in such calculations.
Entropy in molecular recognition by proteins
Proceedings of the National Academy of Sciences of the United States of America, 2017
Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein-ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein-ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein-ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for con...
Configurational Entropy in Protein–Peptide Binding
Journal of Molecular Biology, 2009
Configurational entropy is thought to influence biomolecular processes, but there are still many open questions about this quantity, including its magnitude, its relationship to molecular structure, and the importance of correlation. The mutual information expansion (MIE) provides a novel and systematic approach to computing configurational entropy changes due to correlated motions from molecular simulations. Here, we present the first application of the MIE method to protein-ligand binding, using multiple molecular dynamics simulations (MMDSs) to study association of the UEV domain of the protein Tsg101 and an HIV-derived nonapeptide. The current investigation utilizes the second-order MIE approximation, which treats correlations between all pairs of degrees of freedom. The computed change in configurational entropy is large and is found to have a major contribution from changes in pairwise correlation. The results also reveal intricate structure-entropy relationships. Thus, the present analysis suggests that, in order for a model of binding to be accurate, it must include a careful accounting of configurational entropy changes.
Computation of entropy contribution to protein-ligand binding free energy
Biochemistry (Moscow), 2007
One of the most important factors limiting the for mation of intermolecular protein-ligand (PL) complexes is the restriction of rotational, translational, and internal degrees of freedom both for ligand and protein. The cor responding contribution to the PL binding free energy ∆G b is mainly due to the change in configurational entropy ∆S config . Computation of ∆S config is a complicated task because the full investigation of available configura tional space is needed. Different simplified approaches are used for computation of ∆S config for real systems.
Journal of Physical Chemistry B, 2018
Entropy calculations represent one of the most challenging steps in obtaining the binding free energy in biomolecular systems. A novel computationally effective approach (IE) was recently proposed to calculate the entropy based on the computation of protein-ligand interaction energy directly from molecular dynamics (MD) simulations. We present a study focused on the application of this method to flexible molecular systems and compare its performance with well-established normal mode (NM) and quasiharmonic (QH) entropy calculation approaches. Our results raise substantial concerns on the general applicability of IE in terms of reproducibility, reasonable absolute values of the entropy and agreement with NM and QM approaches. IE shows significant variation in the computed entropy values depending on the MD frames chosen for calculations. These deviations render reproducibility of IE calculations to be far from sufficient. We conclude that IE is recommended to be used after substantial modifications with respect to its sampling methodology.
Journal of medicinal chemistry, 2018
Biophysical parameters can accelerate drug development; e.g., rigid ligands may reduce entropic penalty and improve binding affinity. We studied systematically the impact of ligand rigidification on thermodynamics using a series of fasudil derivatives inhibiting protein kinase A by crystallography, isothermal titration calorimetry, nuclear magnetic resonance, and molecular dynamics simulations. The ligands varied in their internal degrees of freedom but conserve the number of heteroatoms. Counterintuitively, the most flexible ligand displays the entropically most favored binding. As experiment shows, this cannot be explained by higher residual flexibility of ligand, protein, or formed complex nor by a deviating or increased release of water molecules upon complex formation. NMR and crystal structures show no differences in flexibility and water release, although strong ligand-induced adaptations are observed. Instead, the flexible ligand entraps more efficiently water molecules in s...