Coarse-Grained Prediction of Peptide Binding to G‑Protein Coupled Receptors

In this study, we used the Martini Coarse-Grained model with no applied restraints to predict the binding mode of some peptides to G-Protein Coupled Receptors (GPCRs). Both the Neurotensin-1 and the chemokine CXCR4 receptors were used as test cases. Their ligands, NTS_8–13 and CVX15 peptides, respectively, were initially positioned in the surrounding water box. Using a protocol based on Replica Exchange Molecular Dynamics (REMD), both opening of the receptors and entry of the peptides into their dedicated pockets were observed on the μs time-scale. After clustering, the most statistically representative orientations were closely related to the X-ray structures of reference, sharing both RMSD lower than 3 Å and most of the native contacts. These results demonstrate that such a model, that does not require access to tremendous computational facilities, can be helpful in predicting peptide binding to GPCRs as well as some of the receptor’s conformational changes required for this key step. We also discuss how such an approach can now help to predict, <i>de novo</i>, the interactions of GPCRs with other intra- or extracellular peptide/protein partners

Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Neurotensin exerts potent analgesia by acting at both NTS1 and NTS2 receptors, whereas NTS1 activation also results in other physiological effects such as hypotension and hypothermia. Here, we used molecular modeling approach to design highly selective NTS2 ligands by investigating the docking of novel NT­[8-13] compounds at both NTS1 and NTS2 sites. Molecular dynamics simulations revealed an interaction of the Tyr¹¹ residue of NT­[8-13] with an acidic residue (Glu¹⁷⁹) located in the ECL2 of hNTS2 or with a basic residue (Arg²¹²) at the same position in hNTS1. The importance of the residue at position 11 for NTS1/NTS2 selectivity was further demonstrated by the design of new NT analogues bearing basic (Lys, Orn) or acid (Asp or Glu) function. As predicted by the molecular dynamics simulations, binding of NT­[8-13] analogues harboring a Lys¹¹ exhibited higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212 was substituted by the negatively charged Glu residue

Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Neurotensin exerts potent analgesia by acting at both NTS1 and NTS2 receptors, whereas NTS1 activation also results in other physiological effects such as hypotension and hypothermia. Here, we used molecular modeling approach to design highly selective NTS2 ligands by investigating the docking of novel NT­[8-13] compounds at both NTS1 and NTS2 sites. Molecular dynamics simulations revealed an interaction of the Tyr¹¹ residue of NT­[8-13] with an acidic residue (Glu¹⁷⁹) located in the ECL2 of hNTS2 or with a basic residue (Arg²¹²) at the same position in hNTS1. The importance of the residue at position 11 for NTS1/NTS2 selectivity was further demonstrated by the design of new NT analogues bearing basic (Lys, Orn) or acid (Asp or Glu) function. As predicted by the molecular dynamics simulations, binding of NT­[8-13] analogues harboring a Lys¹¹ exhibited higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212 was substituted by the negatively charged Glu residue