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The pH-dependent conformational states of kyotorphin: a constant-pH molecular dynamics study.

ABSTRACT: An extensive conformational study of the analgesic dipeptide kyotorphin (L-Tyr-L-Arg) at different pH values was performed using a constant-pH molecular dynamics method. This dipeptide showed a remarkable pH-dependent conformational variety. The protonation of the N-terminal amine was identified as a key element in the transition between the more extended and the more packed conformational states, as monitored by the dihedral angle defined by the atoms 1Cbeta-1Calpha-2Calpha-2Cbeta. The principal-component analysis of kyotorphin identified two major conformational populations (the extended trans and the packed cis) together with conformations that occur exclusively at extreme pH values. Other, less stable conformations were also identified, which help us to understand the transitions between the predominant populations. The fitting of kyotorphin's conformational space to the structure of morphine resulted in a set of conformers that were able to fulfill most of the constraints for the mu-receptor. These results suggest that there may be strong similarities between the kyotorphin receptor and the structural family of opioid receptors.

SUBMITTER: Machuqueiro M

PROVIDER: S-EPMC1861802 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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The pH-dependent conformational states of kyotorphin: a constant-pH molecular dynamics study.

Machuqueiro Miguel M Baptista António M AM

Biophysical journal 20061215 6

An extensive conformational study of the analgesic dipeptide kyotorphin (L-Tyr-L-Arg) at different pH values was performed using a constant-pH molecular dynamics method. This dipeptide showed a remarkable pH-dependent conformational variety. The protonation of the N-terminal amine was identified as a key element in the transition between the more extended and the more packed conformational states, as monitored by the dihedral angle defined by the atoms 1Cbeta-1Calpha-2Calpha-2Cbeta. The principa ...[more]

PMID: 17172294

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Project description:Protein-protein association is often mediated by electrostatic interactions and modulated by pH. However, experimental and computational studies have often overlooked the effect of association on the protonation state of the protein. In this work, we present a methodological approach based on constant-pH molecular dynamics (MD), which aims to provide a detailed description of a pH-dependent protein-protein association, and apply it to the dimerization of β-lactoglobulin (BLG). A selection of analyses is performed using the data generated by constant-pH MD simulations of monomeric and dimeric forms of bovine BLG, in the pH range 3-8. First, we estimate free energies of dimerization using a computationally inexpensive approach based on the Wyman-Tanford linkage theory, calculated in a new way through the use of thermodynamically based splines. The individual free energy contribution of each titratable site is also calculated, allowing for identification of relevant residues. Second, the correlations between the proton occupancies of pairs of sites are calculated (using the Pearson coefficient), and extensive networks of correlated sites are observed at acidic pH values, sometimes involving distant pairs. In general, strongly correlated sites are also slow proton exchangers and contribute significantly to the pH-dependency of the dimerization free energy. Third, we use ionic density as a fingerprint of protein charge distribution and observe electrostatic complementarity between the monomer faces that form the dimer interface, more markedly at the isoionic point (where maximum dimerization occurs) than at other pH values, which might contribute to guide the association. Finally, the pH-dependent dimerization modes are inspected using PCA, among other analyses, and two states are identified: a relaxed state at pH 4-8 (with the typical alignment of the crystallographic structure) and a compact state at pH 3-4 (with a tighter association and rotated alignment). This work shows that an approach based on constant-pH MD simulations can produce rich detailed pictures of pH-dependent protein associations, as illustrated for BLG dimerization.

Dataset Information

The pH-dependent conformational states of kyotorphin: a constant-pH molecular dynamics study.

Publications

The pH-dependent conformational states of kyotorphin: a constant-pH molecular dynamics study.

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