Correlated Response of Protein Side-Chain Fluctuations and Conformational Entropy to Ligand Binding

Tatikonda, Rajitha; Saharay, Moumita; Smith, Jeremy C.; Krishnan, Marimuthu

doi:10.1021/acs.jpcb.1c01227

Correlated Response of Protein Side-Chain Fluctuations and Conformational Entropy to Ligand Binding

Journal Article · Mon Aug 23 00:00:00 EDT 2021 · Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry

DOI:https://doi.org/10.1021/acs.jpcb.1c01227· OSTI ID:1817449

Tatikonda, Rajitha ^[1]; Saharay, Moumita ^[2]; ^[1]; ^[3]

Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Hyderabad (India)
International Inst. of Information Technology, Hyderbad, (India)

The heterogeneous fast side-chain dynamics of proteins plays crucial roles in molecular recognition and binding. Site-specific NMR experiments quantify these motions by measuring the model-free order parameter (O_axis²) on a scale of 0 (most flexible) to 1 (least flexible) for each methyl-containing residue of proteins. In this work, we have examined ligand-induced variations in the fast side-chain dynamics and conformational entropy of calmodulin (CaM) using five different CaM–peptide complexes. O_axis² of CaM in the ligand-free (O_axis,U²) and ligand-bound (O_axis,B²) states are calculated from molecular dynamics trajectories and conformational energy surfaces obtained using the adaptive biasing force (ABF) method. ΔO_axis² = O_axis,B² – O_axis,U² follows a Gaussian-like unimodal distribution whose second moment is a potential indicator of the binding affinity of these complexes. The probability for the binding-induced O_axis,U² → O_axis,B² transition decreases with increasing magnitude of ΔO_axis², indicating that large flexibility changes are improbable for side chains of CaM after ligand binding. A linear correlation established between ΔOaxis2 and the conformational entropy change of the protein makes possible the determination of the conformational entropy of binding of protein–ligand complexes. The results not only underscore the functional importance of fast side-chain fluctuations but also highlight key motional and thermodynamic correlates of protein–ligand binding.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1817449

Journal Information:: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Journal Name: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry Journal Issue: 34 Vol. 125; ISSN 1520-6106

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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Correlated Response of Protein Side-Chain Fluctuations and Conformational Entropy to Ligand Binding

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