Abstract
BackgroundTraditional approaches to elucidation of protein structures by Nuclear Magnetic Resonance spectroscopy (NMR) rely on distance restraints also known as Nuclear Overhauser effects (NOEs). The use of NOEs as the primary source of structure determination by NMR spectroscopy is time consuming and expensive. Residual Dipolar Couplings (RDCs) have become an alternate approach for structure calculation by NMR spectroscopy. In previous works, the software package REDCRAFT has been presented as a means of harnessing the information containing in RDCs for structure calculation of proteins. However, to meet its full potential, several improvements to REDCRAFT must be made.ResultsIn this work, we present improvements to REDCRAFT that include increased usability, better interoperability, and a more robust core algorithm. We have demonstrated the impact of the improved core algorithm in the successful folding of the protein 1A1Z with as high as ±4 Hz of added error. The REDCRAFT computed structure from the highly corrupted data exhibited less than 1.0 Å with respect to the X-ray structure. We have also demonstrated the interoperability of REDCRAFT in a few instances including with PDBMine to reduce the amount of required data in successful folding of proteins to unprecedented levels. Here we have demonstrated the successful folding of the protein 1D3Z (to within 2.4 Å of the X-ray structure) using only N-H RDCs from one alignment medium.ConclusionsThe additional GUI features of REDCRAFT combined with the NEF compliance have significantly increased the flexibility and usability of this software package. The improvements of the core algorithm have substantially improved the robustness of REDCRAFT in utilizing less experimental data both in quality and quantity.
Highlights
Traditional approaches to elucidation of protein structures by Nuclear Magnetic Resonance spectroscopy (NMR) rely on distance restraints known as Nuclear Overhauser effects (NOEs)
The use of Residual Dipolar Coupling (RDC) data acquired from Nuclear Magnetic Resonance (NMR) spectroscopy has become a potential avenue for a significant reduction in the cost of structure determination of proteins [7]
RDC data have been demonstrated to overcome some long-standing challenges in NMR spectroscopy such as structure determination of membrane proteins [10,11,12,13,14], recognition of fold families [15] and the concurrent study of structure and dynamics of proteins [16,17,18,19,20,21,22,23,24]
Summary
Traditional approaches to elucidation of protein structures by Nuclear Magnetic Resonance spectroscopy (NMR) rely on distance restraints known as Nuclear Overhauser effects (NOEs). While it has been estimated that 30% of the human proteome consists of membrane proteins, this important class of proteins is represented by approximately 120 proteins in current databases [6, 7] Such observed disparities are rooted in the lack of new approaches to structure calculation that overcomes the existing barriers in structural determination of proteins [8, 9]. The use of Residual Dipolar Coupling (RDC) data acquired from Nuclear Magnetic Resonance (NMR) spectroscopy has become a potential avenue for a significant reduction in the cost of structure determination of proteins [7]. The REDCRAFT package is purely developed in C++ according to valid software development principles and is freely available for download via Bitbucket repository (https://bitbucket.org/hvalafar/redcraft/)
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