BIOPHYSICAL THEORY AND MODELING |
Equilibrium structure and folding of a helix-forming peptide: Circular dichroism measurements and replica-exchange molecular dynamics simulations
Krzysztof Kuczera 1* and Gouri S Jas 1
1 University of Kansas
* To whom correspondence should be addressed. E-mail: kkuczera{at}ku.edu.
Submitted on May 4, 2004
Revised on July 1, 2004
Accepted on 10 August 2004
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Abstract |
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We have performed experimental measurements and computer simulations of the equilibrium structure and folding of a 21-residue alpha-helical heteropeptide. Far UV circular dichroism spectroscopy is used to identify the presence of helical structure and to measure the thermal unfolding curve. The observed melting temperature is 296 K, with a folding enthalpy of -11.6 kcal/mol and entropy of -39.6 cal/(mol K). Our simulations involve 45 ns of replica exchange molecular dynamics of the peptide, using 8 replicas at temperatures between 280 and 450 K, and the program CHARMM with a continuum solvent model. In a 30 ns simulation started from a helical structure, conformational equilibrium at all temperatures was reached after 15 ns. This simulation was used to calculate the peptide melting curve, predicting a folding transition with a melting temperature in the 330-350 K range, enthalpy change of -10 kcal/mol and entropy change of -30 cal/(mol K). The simulation results were also used to analyze the peptide structural fluctuations and the free energy surface of helix unfolding. In a separate 15 ns replica exchange molecular dynamics simulation started from the extended structure, the helical conformation was first attained after about 2.8 ns, and equilibrium was reached after 10 ns of simulation. These results showed a sequential folding process with a systematic increase in the number of hydrogen bonds until the helical state is reached, and confirmed that the alpha-helical state is the global free energy minimum for the peptide at low temperatures.
Key Words:
circular dichroism, helix formation, heteropeptide, replica exchange molecular dynamics
