Resolution-adapted recombination of structural features significantly improves sampling in restraint guided structure calculation

By Oliver F. Lange, David Baker. 2011

80 citations recorded by the source corpus.

Recent work has shown that NMR structures can be determined by integrating sparse NMR data with structure prediction methods such as Rosetta. The experimental data serve to guide the search for the lowest energy state towards the deep minimum at the native state which is frequently missed in Rosetta de novo structure calculations. However, as the protein size increases, sampling again becomes limiting; for example, the standard Rosetta protocol involving Monte Carlo fragment insertion starting from an extended chain fails to converge for proteins over 150 amino acids even with guidance from chemical shifts (CS‐Rosetta) and other NMR data. The primary limitation of this protocol—that every folding trajectory is completely independent of every other—was recently overcome with the development of a new approach involving resolution‐adapted structural recombination (RASREC). Here we describe the RASREC approach in detail and compare it to standard CS‐Rosetta. We show that the improved sampling of RASREC is essential in obtaining accurate structures over a benchmark set of 11 proteins in the 15‐25 kDa size range using chemical shifts, backbone RDCs and HN‐HN NOE data; in a number of cases the improved sampling methodology makes a larger contribution than incorporation of additional experimental data. Experimental data are invaluable for guiding sampling to the vicinity of the global energy minimum, but for larger proteins, the standard Rosetta fold‐from‐extended‐chain protocol does not converge on the native minimum even with experimental data and the more powerful RASREC approach is necessary to converge to accurate solutions. Proteins 2011. © 2012 Wiley Periodicals, Inc.

Subfields: Materials Chemistry, Molecular Biology, Spectroscopy

Citations in the corpus

• CS-ROSETTA (2018, unknown): “RASREC is an iterative Abrelax protocol, which exploits the features of intermediate structures to build self-consistent core of a protein that resembles the native fold (Lange & Baker, 2012).”
• Automatic NOESY assignment in CS-RASREC-Rosetta (2014, unknown): “We have implemented an algorithm for automatic NOE assignment in ROSETTA and coupled it with the iterative conformational sampling method RASREC.”
• Chemical shift-based methods in NMR structure determination (2018, unknown): “Whereas MFR [62], CHESHIRE [59] and CS-Rosetta [60,82] utilize chemical shifts in conjunction with known structures to derive a selection of low-resolution backbone fragments, they do not take full advantage of the high resolution structural information encoded within the data.”
• Pseudocontact Shift-Driven Iterative Resampling for 3D Structure Determinations of Large Proteins. (2016, unknown): “The first approach used RASREC Rosetta [7,10] with NOE restraints generated using perdeuterated samples in combination with C-methyl labeling of the amino acids isoleucine, leucine, valine, alanine, methionine and threonine [35].”
• The structure of mouse cytomegalovirus m04 protein determined from sparse NMR data reveals a new fold of the m02-m06 family of viral immune modulators (2014, unknown): “We used the recently developed RASREC protocol (Lange and Baker, 2012), guided by the backbone CSs, a total of 67 long-range NOE distance restraints (23 HN-HN, 25 CH3-CH3, and 19 H N-CH3) and 231 RDCs from two alignment media as N-H vector orientation restraints.”