We have performed experimental measurements and computer simulations of the equilibrium structure and folding of a 21-residue α-helical heteropeptide. Far ultraviolet circular dichroism spectroscopy is used to identify the presence of helical structure and to measure the thermal unfolding curve. The observed melting temperature is 296K, with a folding enthalpy of −11.6kcal/mol and entropy of −39.6cal/(mol K). Our simulations involve 45ns of replica-exchange molecular dynamics of the peptide, using eight replicas at temperatures between 280 and 450K, 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 15ns. This simulation was used to calculate the peptide melting curve, predicting a folding transition with a melting temperature in the 330–350K range, enthalpy change of −10kcal/mol, and entropy change of −30cal/(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 ∼2.8ns, and equilibrium was reached after 10ns 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 α-helical state is the global free-energy minimum for the peptide at low temperatures.