M-ZDOCK: A grid-based approach for Cn symmetric multimer docking

Bioinformatics Program, Boston University, Boston, MA, USA.
Bioinformatics (Impact Factor: 4.62). 05/2005; 21(8):1472-8. DOI: 10.1093/bioinformatics/bti229
Source: PubMed

ABSTRACT Computational protein docking is a useful technique for gaining insights into protein interactions. We have developed an algorithm M-ZDOCK for predicting the structure of cyclically symmetric (Cn) multimers based on the structure of an unbound (or partially bound) monomer. Using a grid-based Fast Fourier Transform approach, a space of exclusively symmetric multimers is searched for the best structure. This leads to improvements both in accuracy and running time over the alternative, which is to run a binary docking program ZDOCK and filter the results for near-symmetry. The accuracy is improved because fewer false positives are considered in the search, thus hits are not as easily overlooked. By searching four instead of six degrees of freedom, the required amount of computation is reduced. This program has been tested on several known multimer complexes from the Protein DataBank, including four unbound multimers: three trimers and a pentamer. For all of these cases, M-ZDOCK was able to find at least one hit, whereas only two of the four testcases had hits when using ZDOCK and a symmetry filter. In addition, the running times are 30-40% faster for M-ZDOCK. AVAILABILITY: M-ZDOCK is freely available to academic users at CONTACT: SUPPLEMENTARY INFORMATION:

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    • "Only a small number methods exist for docking more than two monomers. These methods attempt to make the search for the correct docking configuration tractable by focusing on symmetric complexes [10] or by extending pairwise solutions via combinatorially assembling monomers incrementally, using greedy heuristics to cut down the search space such as selecting only a subset of the complexes of size k and pass them to the next stage as candidates to search for a complex of size k + 1, or generating pairwise docking results and expanding them using a minimum spanning tree [11,12]. "
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    ABSTRACT: We 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. Our 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. Evolutionary 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.
    BMC Structural Biology 11/2013; 13 Suppl 1(Suppl 1):S7. DOI:10.1186/1472-6807-13-S1-S7 · 2.22 Impact Factor
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    • "The assembly of the modelled MCU subunits was performed using the symmetric multimer docking program M - ZDOCK ( Pierce et al , 2005 ) . Channel forming proposed solutions were analysed and the best scoring ones , according to energetic criteria , have been subjected to a simulated annealing minimization using Yasara Structure Suite ( v . "
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    ABSTRACT: Mitochondrial calcium uniporter (MCU) channel is responsible for Ruthenium Red-sensitive mitochondrial calcium uptake. Here, we demonstrate MCU oligomerization by immunoprecipitation and Förster resonance energy transfer (FRET) and characterize a novel protein (MCUb) with two predicted transmembrane domains, 50% sequence similarity and a different expression profile from MCU. Based on computational modelling, MCUb includes critical amino-acid substitutions in the pore region and indeed MCUb does not form a calcium-permeable channel in planar lipid bilayers. In HeLa cells, MCUb is inserted into the oligomer and exerts a dominant-negative effect, reducing the [Ca(2+)]mt increases evoked by agonist stimulation. Accordingly, in vitro co-expression of MCUb with MCU drastically reduces the probability of observing channel activity in planar lipid bilayer experiments. These data unveil the structural complexity of MCU and demonstrate a novel regulatory mechanism, based on the inclusion of dominant-negative subunits in a multimeric channel, that underlies the fine control of the physiologically and pathologically relevant process of mitochondrial calcium homeostasis.
    The EMBO Journal 07/2013; 32(17). DOI:10.1038/emboj.2013.157 · 10.75 Impact Factor
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    • "To tackle this problem, several solutions have been proposed to date. Some approaches, such as SymmDock (Schneidman- Duhovny et al., 2005), M-ZDOCK (Pierce et al., 2005), or MolFit (Berchanski et al., 2005), exploit the fact that multimers often respect a specific symmetry (Plaxco and Gross, 2009; Goodsell and Olson, 2000). These methods reduce the search space by imposing a specific symmetry and subsequently rigidly dock the binding partners so that a predefined energy function is minimized . "
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    ABSTRACT: Proteins often assemble in multimeric complexes to perform a specific biologic function. However, trapping these high-order conformations is difficult experimentally. Therefore, predicting how proteins assemble using in silico techniques can be of great help. The size of the associated conformational space and the fact that proteins are intrinsically flexible structures make this optimization problem extremely challenging. Nonetheless, known experimental spatial restraints can guide the search process, contributing to model biologically relevant states. We present here a swarm intelligence optimization protocol able to predict the arrangement of protein symmetric assemblies by exploiting a limited amount of experimental restraints and steric interactions. Importantly, within this scheme the native flexibility of each protein subunit is taken into account as extracted from molecular dynamics (MD) simulations. We show that this is a key ingredient for the prediction of biologically functional assemblies when, upon oligomerization, subunits explore activated states undergoing significant conformational changes.
    Structure 06/2013; 21(7). DOI:10.1016/j.str.2013.05.014 · 6.79 Impact Factor
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