TY - JOUR KW - Computer Simulation KW - Kinetics KW - Models, Molecular KW - Peptides KW - Protein Folding KW - Protein Structure, Secondary KW - Mutation KW - Time Factors KW - Protein Structure, Tertiary KW - Salts KW - Spectrophotometry, Infrared AU - B. Paoli AU - M. Seeber AU - E. H. G. Backus AU - J. A. Ihalainen AU - P. Hamm AU - A. Caflisch AB -

Multiple 4-µs molecular dynamics (MD) simulations are used to study the folding process of the cross-linked α-helical peptide Ac-EACAR5EAAAR10EAACR15Q-NH2 (EAAAR peptide). The folding kinetics are single exponential at 330 K, while they are complex at 281 K with a clear deviation from single-exponential behavior, in agreement with time-resolved infrared (IR) spectroscopy measurements. Network analysis of the conformation space sampled by the MD simulations reveals four main folding channels which start from conformations with partially formed helical structure and non-native salt-bridges in a kinetically partitioned unfolded state. The independent folding pathways explain the comparable quality of models based on stretched exponential and multiexponential fitting of the kinetic traces at low temperature. The rearrangement of bulky side chains, and in particular their reorientation with respect to the cross-linker, makes the EAAAR peptide a slower folder at 281 K than a similar peptide devoid of the three glutamate side chains. On the basis of this simulation result, extracted from a total MD sampling of 1.0 ms, a mutant with additional bulky side chains (three methionines replacing alanines at positions 2, 7, and 12) is suggested to fold slower than the EAAAR peptide. This prediction is confirmed by time-resolved IR spectroscopy.

BT - The Journal of Physical Chemistry B C1 - 0112 DA - 2009 Apr 2 DO - 10.1021/jp810431s IS - 13 J2 - J. Phys. Chem. B LA - eng M3 - Research Article N2 -

Multiple 4-µs molecular dynamics (MD) simulations are used to study the folding process of the cross-linked α-helical peptide Ac-EACAR5EAAAR10EAACR15Q-NH2 (EAAAR peptide). The folding kinetics are single exponential at 330 K, while they are complex at 281 K with a clear deviation from single-exponential behavior, in agreement with time-resolved infrared (IR) spectroscopy measurements. Network analysis of the conformation space sampled by the MD simulations reveals four main folding channels which start from conformations with partially formed helical structure and non-native salt-bridges in a kinetically partitioned unfolded state. The independent folding pathways explain the comparable quality of models based on stretched exponential and multiexponential fitting of the kinetic traces at low temperature. The rearrangement of bulky side chains, and in particular their reorientation with respect to the cross-linker, makes the EAAAR peptide a slower folder at 281 K than a similar peptide devoid of the three glutamate side chains. On the basis of this simulation result, extracted from a total MD sampling of 1.0 ms, a mutant with additional bulky side chains (three methionines replacing alanines at positions 2, 7, and 12) is suggested to fold slower than the EAAAR peptide. This prediction is confirmed by time-resolved IR spectroscopy.

PY - 2009 SP - 4435 EP - 4442 T2 - The Journal of Physical Chemistry B TI - Bulky side chains and non-native salt bridges slow down the folding of a cross-linked helical peptide: A combined molecular dynamics and time-resolved infrared spectroscopy study VL - 113 SN - 1520-6106 ER -