Molecular Dynamics Simulation of Folding of a Short Helical Peptide with Many Charged Residues

Abstract

A molecular dynamics simulation of the folding of conantokin-T (con-T), a short helical peptide with 5 helical turns of 21 amino acids with 10 charged residues, was carried out to examine folding pathways for this peptide and to predict the folding rate. In the 18 trajectories run at 300 K, 16 trajectories folded, with an averaged folding time of approximately 50 ns. Two trajectories did not fold in up to 200 ns simulation. The folded structure in folded trajectories is in good agreement with experimental structure. An analysis of the trajectories showed that, at the beginning of a few nanoseconds, helix formation started from residues 5-9 with assistance of a hydrophobic clustering involving Tyr5, Met8, and Leu9. The peptide formed a U-shape mainly due to charge-charge interactions between charged residues at the N- and C-terminus segments. In the next approximately 10 ns, several nonnative charge-charge interactions were broken and nonnative Gla10-Lys18 (this denotes a salt bridge between Gal10 and Lys18) and/or Gla10-Lys19 interactions appeared more frequently in this folding step and the peptide became a fishhook J-shape. From this structure, the peptide folded to the folded state in 7 of all 16 folded trajectories in approximately 15 ns. Alternatively, in approximately 30 ns, the con-T went to a conformation in an L-shape with 4 helical turns and a kink at the Arg13 and Gla14 segment in the other 9 trajectories. Con-T in the L-shape then required another approximately 15 ns to fold into the folded state. In addition, in overall folding times, the former 7 trajectories folded faster with the total folding times all shorter than 45 ns, while the latter 9 trajectories folded at a time longer than 45 ns, resulting in an average folding time of approximately 50 ns. Two major folding intermediates found in 2 nonfolded trajectories are stabilized by charge clusters of 5 and 6 charged residues, respectively. With inclusion of friction and solvent-solvent interactions, which were ignored in the present GB/SA solvation model, the folding time obtained above should be multiplied by a factor of 1.25-1.7 according to a previous, similar simulation study. This results in a folding time of 65-105 ns, slightly shorter than the folding time of 127 ns for an alanine-based peptide of the same length. This suggests that the energy barrier of folding for this type of peptides with many charged residues is slightly lower than alanine-based helical peptides by less than 1 kcal/mol.

The Effect of Charge-Charge Interactions on the Kinetics of α-Helix Formation

“…Taken together, these results thus suggest that Con-T does fold on a timescale that is slower than that of alanine-based peptides and the requirement for formation of salt bridges in the rate-limiting step retards the rate of helix formation. Interestingly, this picture is contrary to the conclusion of Wei et al (27), who performed molecular dynamics simulations of Con-T folding. When compared to results of folding simulations of alanine-based peptides of the same length (36), their results suggest that Con-T folds at a faster rate as a result of the salt bridges.…”

“…For example, a variety of spectroscopic methods have been employed to examine the nanosecond folding dynamics of monomeric a-helices in response to a conformational trigger, such as a temperature jump (T-jump) (2)(3)(4)(5)(6)(7)(8)(9)(10)14,16,23), a pH jump (22), or a photo-triggering event (17). In addition, numerous theoretical studies and computer simulations have also been carried out, with the aim of understanding the underlying energy landscape and mechanism governing a-helix folding (1,(11)(12)(13)15,(18)(19)(20)(21)(24)(25)(26)(27)(28). However, our current understanding of the folding dynamics of monomeric a-helices in solution is mostly founded upon studies of alanine-based peptides.…”

On the Foldability of Tryptophan-Containing Tetra- and Pentapeptides: An Exhaustive Molecular Dynamics Study

“…Peptide folding simulations − have evolved to a highly active research field because their significance is threefold: peptides serve as model systems to optimize and validate force fields, − as model systems to study the protein folding problem, − and as potential candidates in drug design studies. − Fast-folding miniproteins are the new “play toys” because their folding can be approximated by both theory and experiment. − …”

The SAAP force field: Development of the single amino acid potentials for 20 proteinogenic amino acids and Monte Carlo molecular simulation for short peptides

“…Computational molecular simulation by using force field parameters [1][2][3][4] has been widely applied in the fields of peptide and protein research for the purposes, such as to complement the structural and thermodynamic information obtained by experiments, [5][6][7][8][9][10] to predict the folding pathways and the interactions with a substrate in solution, [11][12][13][14] and to analyze the fluctuating motions under certain thermodynamic conditions. 15,16 The most advantageous feature of the molecular simulation is the feasibility to depict a picture of a biological phenomenon in the atomic resolution.…”