Error Tolerant NMR Backbone Resonance Assignment and Automated Structure Generation

Abstract

Error tolerant backbone resonance assignment is the cornerstone of the NMR structure determination process. Although a variety of assignment approaches have been developed, none works sufficiently well on noisy fully automatically picked peaks to enable the subsequent automatic structure determination steps. We have designed an integer linear programming (ILP) based assignment system (IPASS) that has enabled fully automatic protein structure determination for four test proteins. IPASS employs probabilistic spin system typing based on chemical shifts and secondary structure predictions. Furthermore, IPASS extracts connectivity information from the inter-residue information and the (automatically picked) (15)N-edited NOESY peaks which are then used to fix reliable fragments. When applied to automatically picked peaks for real proteins, IPASS achieves an average precision and recall of 82% and 63%, respectively. In contrast, the next best method, MARS, achieves an average precision and recall of 77% and 36%, respectively. The assignments generated by IPASS are then fed into our protein structure calculation system, FALCON-NMR, to determine the 3D structures without human intervention. The final models have backbone RMSDs of 1.25Å, 0.88Å, 1.49Å, and 0.67Å to the reference native structures for proteins TM1112, CASKIN, VRAR, and HACS1, respectively. The web server is publicly available at http://monod.uwaterloo.ca/nmr/ipass.

Can We Determine a Protein Structure Quickly?

“…Here is a formal definition of the problem [55] . Given an amino acid sequence of a protein with n residues as r 1 r 2 .…”

“…We have designed a prototype system IPASS for this purpose. IPASS has the following components, as described in [55].…”

A Sequence-Based Dynamic Ensemble Learning System for Protein Ligand-Binding Site Prediction

“…So far, nuclear magnetic resonance (NMR) spectroscopy [2], [3], [4], [5], [6], [7], [8], [9] and X-ray crystallography [10] have been used to determine protein structures. Pintacuda et al employed lanthanide ions for the determination of protein-ligand binding sites [2].…”

Determining Protein Structures from NOESY Distance Constraints by Semidefinite Programming

“…As a result, the NMR method relies heavily on complex computational algorithms. The existing methods for protein NMR can be categorized into four major groups: (i) methods based on Euclidean distance matrix completion (EDMC) (Braun et al, 1981;Havel and Wüthrich, 1984;Biswas et al, 2008;Leung and Toh, 2009); (ii) methods based on molecular dynamics and simulated annealing (Nilges et al, 1988;Brünger, 1993;Güntert et al, 1997;Schwieters et al, 2003;Güntert, 2004); (iii) methods based on local/global optimization (Braun and Go, 1985;Moré and Wu, 1997;Williams et al, 2001); and (iv) methods originating from sequence-based protein structure prediction algorithms (Shen et al, 2008;Raman et al, 2010;Alipanahi et al, 2011).…”