Integrating NOE and RDC using sum-of-squares relaxation for protein structure determination

TL;DR

This paper introduces SOS relaxation methods for integrating NOE and RDC data in NMR-based protein structure determination, achieving exact solutions efficiently and approaching theoretical resolution limits.

Contribution

It develops polynomial-time SOS algorithms for non-convex optimization in protein structure determination, improving accuracy and computational efficiency over existing methods.

Findings

SOS algorithms recover exact solutions in many cases

Methods attain the Cramer-Rao bound with noisy data

Successful application to ubiquitin structure determination

Abstract

We revisit the problem of protein structure determination from geometrical restraints from NMR, using convex optimization. It is well-known that the NP-hard distance geometry problem of determining atomic positions from pairwise distance restraints can be relaxed into a convex semidefinite program. Often the NOE distance restraints are too imprecise and sparse for accurate structure determination. Residual dipolar coupling (RDC) measurements provide additional geometric information on the angles between atom-pair directions and axes of the principal-axis-frame. The optimization problem involving RDC is highly non-convex and requires a good initialization even within the simulated annealing framework. In this paper, we model the protein backbone as an articulated structure composed of rigid units. Determining the rotation of each rigid unit gives the full protein structure. We propose solving the non-convex optimization problems using the sum-of-squares (SOS) hierarchy. The two algorithms - RDC-SOS and RDC-NOE-SOS, have polynomial time complexity in the number of amino-acid residues and run efficiently on a standard desktop. In many instances, the proposed methods exactly recover the solution to the original non-convex optimization problem. We introduce a statistical tool, the Cramer-Rao bound (CRB), to provide an information theoretic bound on the highest resolution one can hope to achieve when determining protein structure from noisy measurements using any methodology. Our simulation results show that when the RDC measurements are corrupted by Gaussian noise of realistic variance, both SOS based algorithms attain the CRB. We successfully apply our method in a divide-and-conquer fashion to determine the structure of ubiquitin from experimental NOE and RDC measurements, achieving more accurate and faster reconstructions compared to the current state of the art.