A study of Barstar folding events using boundary value simulations

Abstract

This study revolves around a computational algorithm called SDEL (Stochastic Difference Equation in Length) that generates approximate protein folding trajectories on the atomically detailed resolution scale. The protein studied is Barstar-a barnase inhibitor. Because of the protein's interesting structure (four alpha helices, three beta strands) and relatively small size (89 residues), Barstar is an optimal choice for running complete folding trajectories on a computer. 12 pathways were generated with SDEL, starting from a structurally wide selection of unfolded conformations, yet all ending with the native configuration. We tracked hydrogen bonds, dihedral angles, native and non-native contacts, and energetic along these folding pathways. The resulting trajectories show: 1) Barstar follows the Hydrophobic Collapse folding scenario, 2) native α-helices begin forming earlier in the trajectory than the β-sheets, 3) particular residues maintain a propensity for helical structure in their unfolded state, and 4) specific non-native contacts persist during the folding trajectory. Strong correlations were found between the SDEL pathways and data from NMR, CD, and other experimental studies.

Fast Photochemical Oxidation of Proteins and Mass Spectrometry Follow Submillisecond Protein Folding at the Amino-Acid Level

“…The above two proposals seem to be contradictory on whether the helix has formed during the initial folding, likely owing to different experiment conditions, but they agree on the folding model of barstar. Recently, simulations applied to barstar show that helix 1 , of all possible regions and secondary structures, is the first to form 6 .…”

“…Recently, simulations applied to barstar show that helix 1 , of all possible regions and secondary structures, is the first to form. 6 Recent advances in mass spectrometry (MS)-based protein footprinting have produced methods that allow study of folding by examining solvent accessibility as an indicator of protein conformational change, assessed by corresponding changes in footprinting extents that are measured by MS. 27,28 Although the overall change of solvent accessibility is reflected by a global mass measurement, 29 the information on individual residues is more valuable in determining regional structure changes. Our hypothesis is that these changes can be probed by FPOP and revealed by bottom-up proteomic analysis of such protein samples.…”

“…In the framework model, secondary structures form during the early stages of folding, and they guide the slow development of the tertiary structure . One way of overcoming the difficulty of experimentally accessing the early folding events is to examine folding mechanisms in silico via molecular dynamics and simulations of folding. − There is experimental evidence that many globular proteins (e.g., myoglobin and staphylococcal nuclease) follow the partial hydrophobic collapse model while folding. Accompanying the dynamics with temperature-jump experimental verification provides a valuable picture for folding events in the low microsecond time frame to show the fastest folding β-sheet protein. , …”

Computer Simulations of the Refolding of Sperm Whale Apomyoglobin from High-Temperature Denaturated State

“…With the knowledge of the native and unfolded structures, the folding trajectories were computed with the SDEL algorithm. This method has been applied to the study of protein folding for three smaller proteins: protein A, cytochrome c , and barstar . SDEL is a boundary value formalism, based on the classical mechanics least-action principle.…”

“…This method has been applied to the study of protein folding for three smaller proteins: protein A, 38 cytochrome c, 39 and barstar. 40 SDEL is a boundary value formalism, based on the classical mechanics least-action principle. The starting point of the algorithm is the classical action parametrized as a function of the length of the trajectory: 41…”