Molecular dynamics (MD) simulation is a powerful method for examining the conformational states of biomolecular systems. In the present work, MD simulations were employed to probe into the dynamic modes and conformational states of contryphan-Sm (a Conus venom peptide with D-Trp4) and its analog, [L-Trp4]contryphan-Sm, specifically focusing on the investigation of their structural differences. Molecular modeling showed that the basic cyclic structures of contryphan-Sm and [L-Trp4]contryphan-Sm were similar, with no steric clashes occurring among the amino acid residues. The MD simulations showed that contryphan-Sm assumed a more compact conformation compared to [L-Trp4]contryphan-Sm based on their maximum peptide dimensions and radii of gyration. After ~ 20 ns of MD simulations, the root-mean-square deviation (RMSD) values were lower for almost all of the amino acid residues in contryphan-Sm, with its D-Trp4 showing the highest difference in RMSD from L-Trp4 in [L-Trp4]contryphan-Sm, suggesting that contryphan-Sm had less structural variability. Energy measurements supported this finding, with contryphan-Sm consistently exhibiting lower kinetic energy values compared to [L-Trp4]contryphan-Sm throughout the MD simulations. The Ramachandran plots showed greater variations in phi or psi angles in L-Trp4, Gln5, Pro6 and Trp7 in [L-Trp4]contryphan-Sm than the corresponding residues in contryphan-Sm at the start and end of the MD simulations. Contryphan-Sm showed less solvent accessibility than [L-Trp4]contryphan-Sm as shown by the measurements of their solvent-activated surface areas. Decreased solvent accessibility may be linked to the stacked conformation adopted by contryphan-Sm, aligning D-Trp4, Pro6 and Trp7. Despite the observed motions of the Trp side chains, both contryphan-Sm and [L-Trp4]contryphan-Sm structures do not support the occurrence of intramolecular covalent crosslinking between D/L-Trp4 and Trp7. The observed differences in dynamic modes and conformational states of contryphan-Sm and [L-Trp4]contryphan-Sm are correlated with the greater structural stability of the D-Trp-containing contryphan.
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