title: A molecular interpretation of 2D IR protein folding experiments with Markov state models.
abstract: The folding mechanism of the N-terminal domain of ribosomal protein L9 (NTL91-39) is studied using temperature-jump (T-jump) amide I' two-dimensional infrared (2D IR) spectroscopy in combination with spectral simulations based on a Markov state model (MSM) built from millisecond-long molecular dynamics trajectories. The results provide evidence for a compact well-structured folded state and a heterogeneous fast-exchanging denatured state ensemble exhibiting residual secondary structure. The folding rate of 26.4 μs(-1) (at 80°C), extracted from the T-jump response of NTL91-39, compares favorably with the 18 μs(-1) obtained from the MSM. Structural decomposition of the MSM and analysis along the folding coordinate indicates that helix-formation nucleates the global folding. Simulated difference spectra, corresponding to the global folding transition of the MSM, are in qualitative agreement with measured T-jump 2D IR spectra. The experiments demonstrate the use of T-jump 2D IR spectroscopy as a valuable tool for studying protein folding, with direct connections to simulations. The results suggest that in addition to predicting the correct native structure and folding time constant, molecular dynamics simulations carried out with modern force fields provide an accurate description of folding mechanisms in small proteins.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Baiz
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California.
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Chunte Sam
authors.initials: CS
authors.lastname: Peng
authors.affiliation: Biophysics Program, Stanford University, Stanford, California.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Beauchamp
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, Pennsylvania.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Voelz
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California; Biophysics Program, Stanford University, Stanford, California; Department of Structural Biology, Stanford University, Stanford, California.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts. Electronic address: tokmakoff@uchicago.edu.
authors.forename: Andrei
authors.initials: A
authors.lastname: Tokmakoff
mesh_terms: D000595:Amino Acid Sequence; D003627:Data Interpretation, Statistical; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012269:Ribosomal Proteins / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D012269:Ribosomal Proteins; C049650:ribosomal protein L9