A conservation and biophysics guided stochastic approach to refining docked multimeric proteins

Abstract

BackgroundWe introduce a protein docking refinement method that accepts complexes consisting of any number of monomeric units. The method uses a scoring function based on a tight coupling between evolutionary conservation, geometry and physico-chemical interactions. Understanding the role of protein complexes in the basic biology of organisms heavily relies on the detection of protein complexes and their structures. Different computational docking methods are developed for this purpose, however, these methods are often not accurate and their results need to be further refined to improve the geometry and the energy of the resulting complexes. Also, despite the fact that complexes in nature often have more than two monomers, most docking methods focus on dimers since the computational complexity increases exponentially due to the addition of monomeric units.ResultsOur results show that the refinement scheme can efficiently handle complexes with more than two monomers by biasing the results towards complexes with native interactions, filtering out false positive results. Our refined complexes have better IRMSDs with respect to the known complexes and lower energies than those initial docked structures.ConclusionsEvolutionary conservation information allows us to bias our results towards possible functional interfaces, and the probabilistic selection scheme helps us to escape local energy minima. We aim to incorporate our refinement method in a larger framework which also enables docking of multimeric complexes given only monomeric structures.

AccuRMSD

“…Examples include SwarmDock which uses normal mode analysis [13], and Firedock [15] which uses side-chain flexible refinement combined with soft rigid-body optimization and partial electrostatic interaction energy. A recent docking refinement method [1,2] uses a scoring function that includes an evolutionary traces (ET) term [23,17], in addition to the VdW and electrostatic component. The assumption is that binding interfaces tend to be evolutionary conserved due to their importance.…”

Attenuated Total Reflection Fourier Transform Infrared (ATR FT-IR) Spectroscopy as an Analytical Method to Investigate the Secondary Structure of a Model Protein Embedded in Solid Lipid Matrices

“…However, they present formulation challenges due to the conformational changes that may occur during processing into a dosage form. [1][2][3] Several analytical techniques namely X-ray crystallography, nuclear magnetic resonance (NMR), circular dichroism (CD), Raman spectroscopy, fluorescence spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy can be employed for the analysis of protein conformational changes in the solution form. 4 However, the choice of analytical methods becomes limited when the analysis of protein conformational perturbations in the solid-state formulations is required.…”