(Thermo)dynamic Role of Receptor Flexibility, Entropy, and Motional Correlation in Protein–Ligand Binding

Baron, Riccardo; McCammon, J. Andrew

doi:10.1002/cphc.200700857

Cited by 38 publications

(57 citation statements)

References 51 publications

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“…The conclusion that correlation contributes significantly to configurational entropy differences is consistent with a prior quasiharmonic study using Cartesian coordinates 7 and with MIE 23,24 studies using bond-angle-torsion coordinates. It is also consistent with a recent study that applied MIST to side-chain rotameric states across a series of different proteins.…”

Section: Discussionsupporting

confidence: 87%

Correlation as a Determinant of Configurational Entropy in Supramolecular and Protein Systems

et al. 2014

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For biomolecules in solution, changes in configurational entropy are thought to contribute substantially to the free energies of processes like binding and conformational change. In principle, the configurational entropy can be strongly affected by pairwise and higher-order correlations among conformational degrees of freedom. However, the literature offers mixed perspectives regarding the contributions that changes in correlations make to changes in configurational entropy for such processes. Here we take advantage of powerful techniques for simulation and entropy analysis to carry out rigorous in silico studies of correlation in binding and conformational changes. In particular, we apply information-theoretic expansions of the configurational entropy to well-sampled molecular dynamics simulations of a model host–guest system and the protein bovine pancreatic trypsin inhibitor. The results bear on the interpretation of NMR data, as they indicate that changes in correlation are important determinants of entropy changes for biologically relevant processes and that changes in correlation may either balance or reinforce changes in first-order entropy. The results also highlight the importance of main-chain torsions as contributors to changes in protein configurational entropy. As simulation techniques grow in power, the mathematical techniques used here will offer new opportunities to answer challenging questions about complex molecular systems.

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Section: Discussionsupporting

confidence: 87%

Correlation as a Determinant of Configurational Entropy in Supramolecular and Protein Systems

et al. 2014

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“…The extent of this induced conformational entropy has been shown to control the affinity [36]. These studies, among others [37][38][39][40], support the validity of ligand binding through entropic expansion for disordered proteins.…”

Section: Thermodynamics Of Protein-ligand Bindingmentioning

confidence: 70%

Targeting disordered proteins with small molecules using entropy

Heller

Sormanni

Vendruscolo

2015

Trends in Biochemical Sciences

100

114

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The human proteome includes many disordered proteins. Although these proteins are closely linked with a range of human diseases, no clinically approved drug targets them in their monomeric forms. This situation arises, at least in part, from the current lack of understanding of the mechanisms by which small molecules bind proteins that do not fold into well-defined conformations. To explore possible solutions to this problem, we discuss quite generally how an overall decrease in the free energy associated with intermolecular binding can originate from different combinations of enthalpic and entropic contributions. We then consider more specifically a mechanism of binding by which small molecules can affect the conformational space of a disordered protein by creating an entropic expansion in which more conformations of the protein become populated.

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“…Such a behavior of two entropy estimation approaches used here is inline with the known fact that QH gives an upper bound of conformational entropy, while the entropy approximated just based on dihedral angles' distributions usually represents an underestimate of the real value. 18,53 First, we observed that both S conf -QH and S conf -dihedral are decreased by monomers as compared to the "pure" bilayer ( Figure S8, lower panels), and this effect has a reverse correspondence to the observed heterogeneity increase upon monomer inclusions ( Figure S8, upper panels). The change in both conformational entropies is also negative for all dimers as compared to the pure bilayer.…”

Section: Journal Of Chemical Theory and Computationmentioning

confidence: 73%

Adaptable Lipid Matrix Promotes Protein–Protein Association in Membranes

Kuznetsov

Polyansky

Fleck

et al. 2015

J. Chem. Theory Comput.

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The cell membrane is "stuffed" with proteins, whose transmembrane (TM) helical domains spontaneously associate to form functionally active complexes. For a number of membrane receptors, a modulation of TM domains' oligomerization has been shown to contribute to the development of severe pathological states, thus calling for detailed studies of the atomistic aspects of the process. Despite considerable progress achieved so far, several crucial questions still remain: How do the helices recognize each other in the membrane? What is the driving force of their association? Here, we assess the dimerization free energy of TM helices along with a careful consideration of the interplay between the structure and dynamics of protein and lipids using atomistic molecular dynamics simulations in the hydrated lipid bilayer for three different model systems - TM fragments of glycophorin A, polyalanine and polyleucine peptides. We observe that the membrane driven association of TM helices exhibits a prominent entropic character, which depends on the peptide sequence. Thus, a single TM peptide of a given composition induces strong and characteristic perturbations in the hydrophobic core of the bilayer, which may facilitate the initial "communication" between TM helices even at the distances of 20-30 Å. Upon tight helix-helix association, the immobilized lipids accommodate near the peripheral surfaces of the dimer, thus disturbing the packing of the surrounding. The dimerization free energy of the modeled peptides corresponds to the strength of their interactions with lipids inside the membrane being the lowest for glycophorin A and similarly higher for both homopolymers. We propose that the ability to accommodate lipid tails determines the dimerization strength of TM peptides and that the lipid matrix directly governs their association.

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(Thermo)dynamic Role of Receptor Flexibility, Entropy, and Motional Correlation in Protein–Ligand Binding

Cited by 38 publications

References 51 publications

Correlation as a Determinant of Configurational Entropy in Supramolecular and Protein Systems

Correlation as a Determinant of Configurational Entropy in Supramolecular and Protein Systems

Targeting disordered proteins with small molecules using entropy

Adaptable Lipid Matrix Promotes Protein–Protein Association in Membranes

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