A Tree-Based Algorithm for Determining the Effects of Solvation on the Structure of Salivary Gland Tripeptide NH3+-D-PHE-D-GLU-GLY-COO−

Abstract

A D-enantiomeric analog of the submandibular gland rat-1 tripeptide FEG (Seq: NH(3)(+)-Phe-Glu-Gly-COO(-)) called feG (Seq: NH(3)(+)-D-Phe-D-Glu-Gly-COO(-)) was examined by molecular dynamics simulations in water. Previous in vacuo simulations suggested a conformation consisting predominantly of interactions between the Phe side chain and glutamyl-carboxyl group and a carboxyl/amino termini interaction. The solvated peptide was simulated using two approaches which were compared-a single 400-ns simulation and a "simulation tree." The "tree" approach utilized 45 10-ns simulations with different conformations used as initial structures for given trajectories. We demonstrate that multiple short duration simulations are able to describe the same conformational space as that described by longer simulations. Furthermore, previously described in vacuo interactions were confirmed with amendments: the previously described head-to-tail arrangement of the amino and carboxyl termini, was not observed; the interaction between the glutamyl carboxyl and Phe side chain describes only one of a continuum of conformations present wherein the aromatic residue remains in close proximity to the glutamyl carbonyl group, and also interacts with either of the two available carboxyl groups. Finally, utilizing only two separate 10-ns trajectories, we were able to better describe the conformational space than a single 60-ns trajectory, realizing a threefold decrease in the computational complexity of the problem.

A New Conformationally Restricted Mimetic of Dipeptide EG – Synthesis of an Analogue of FEG

“…In fact, the conformational behaviour of 7 was previously studied, and the most probable bioactive conformation for this peptide displays a strong interaction occurring between the glutamyl carboxyl group and the N-terminus of the peptide, together with an interaction between the aromatic ring and the terminal carboxyl group. [6,8] Our results are in total agreement with these findings and prompted us to compare the conformational preferences of the two compounds identifying the most probable bioactive conformation of 1 having the following φ and ψ values (conformer number 1 at lowest energy): φ 1 = -174.0°, ψ 1 = 128.8°; φ 2 = -137.3°, ψ 2 = 126.8°; φ 3 = -179.7°, ψ 3 = -0.40°.…”

“…Within an ongoing research program aimed at preparing conformationally restricted analogues of amino acids or oligopeptides, [4] we hypothesized that mimetics of the salivary gland tripeptide FEG (Phe-Glu-Gly) (1) [5,6] and its enantiomer feG (ent-1), [5,7,8] could be of interest owing to the biological activity of the parent peptides. In fact, FEG was reported to display anti-hypotensive properties against anaphylactic shock, [5] together with a potent inhibition of intestinal anaphylaxis and inhibitory effects on inflammatory reactions.…”

Enhancing Virtual Screening Performance of Protein Kinases with Molecular Dynamics Simulations

“…MD trajectories were aligned on active site alpha carbon atoms using cpptraj. 58, 59 The aligned trajectories were clustered using two different clustering methods: 1) Gromos RMSD-based method 67, 68 and POVME 2.0. 69 …”

“…Residues within 10 Å of the inhibitor were selected and defined as the active site. MD trajectories were aligned on active site α carbon atoms using cpptraj. , The aligned trajectories were clustered using two different clustering methods: (1) a Gromos RMSD-based method , and (2) POVME 2.0 …”

“…MD trajectories were aligned on active site α carbon atoms using cpptraj. 58,59 The aligned trajectories were clustered using two different clustering methods: (1) a Gromos RMSD-based method 67,68 Using the Gromos algorithm, pairwise root-mean-square deviations were calculated for all the active site heavy atoms for each frame. MD frames were clustered together if their RMSD value was below the specified cutoff.…”