Xeno amino acid peptide: MD with NOE restraints
Description
For full details, see the manuscript. Using NMR-informed molecular dynamics, we have observed a propensity towards a short β-bend at the N-terminus (residues v3-a5) and an α-helical structure at the C-terminus (residues a18-a24). The φ and ψ dihedral angles of these residues in 10 representative structures from independent MD replicas suggest a mix of C-terminal α-helix and N-terminal β-bend, except for MD replicate number 4, the least stable structure, where we observe a shorter C-terminal α-helix starting at n20. P2 is thus the first peptide constructed entirely from a xeno amino acid alphabet that has been observed to adopt any secondary structure elements according to CD, MD, and NMR.
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Steps to reproduce
For full details, see the manuscript. Briefly, xeno amino acids were parametrised consistently with the ff19SB AMBER force field. The P2 peptide was modeled in the fully extended formed, capped by acetyl and N-methylamide at the N- and C-termini. The MD parameters were as follows: IGB=5 generalized Born implicit solvation model, implicit ion strength of 0.15 M and infinite cutoff for non-bonded interactions. Minimisation of 5000 cycles was followed by stepwise warming from 5 to 300 K and increasing the NOE restraints weight over 120 ps in NVT ensemble. The timestep of 1 fs was used. The Langevin thermostat with friction coefficient of 1 ps-1 was used. Thereafter, the pmemd.cuda program of Amber24 suite97 was used to run 1.9 µs-long production runs where the timestep was increased to 2 fs. MD was run in 10 independent replicas. Most NOE restraints were satisfied during MD; if we consider a distance violation of up to 0.1 Å, there were only 8 out of 164 which occurred in more than 10% of snapshots; no violation greater than 0.2 Å was observed. From the production MD, it appears that the first 300 ns were needed to achieve stable secondary structures. The first 300 ns of trajectories were therefore omitted from subsequent analysis. The φ and ψ dihedral angles over the last 1.6 μs were averaged for each trajectory so as to find one structure from MD with the highest similarity to the NMR structure. These 10 selected structures underwent 5000 cycles of unrestrained MM/GB5 minimisation to yield the final 10 representative structures (deposited to wwPDB). All the calculations and analyses were conducted using the AMBER24 and AmberTools24 suites.