Accuracy of protein-protein binding sites in high-throughput template-based modeling.

Department of Molecular Biosciences, The University of Kansas, Center for Bioinformatics, Lawrence, Kansas, United States of America.
PLoS Computational Biology (Impact Factor: 4.87). 01/2010; 6(4):e1000727. DOI: 10.1371/journal.pcbi.1000727
Source: PubMed

ABSTRACT The accuracy of protein structures, particularly their binding sites, is essential for the success of modeling protein complexes. Computationally inexpensive methodology is required for genome-wide modeling of such structures. For systematic evaluation of potential accuracy in high-throughput modeling of binding sites, a statistical analysis of target-template sequence alignments was performed for a representative set of protein complexes. For most of the complexes, alignments containing all residues of the interface were found. The full interface alignments were obtained even in the case of poor alignments where a relatively small part of the target sequence (as low as 40%) aligned to the template sequence, with a low overall alignment identity (<30%). Although such poor overall alignments might be considered inadequate for modeling of whole proteins, the alignment of the interfaces was strong enough for docking. In the set of homology models built on these alignments, one third of those ranked 1 by a simple sequence identity criteria had RMSD<5 A, the accuracy suitable for low-resolution template free docking. Such models corresponded to multi-domain target proteins, whereas for single-domain proteins the best models had 5 A<RMSD<10 A, the accuracy suitable for less sensitive structure-alignment methods. Overall, approximately 50% of complexes with the interfaces modeled by high-throughput techniques had accuracy suitable for meaningful docking experiments. This percentage will grow with the increasing availability of co-crystallized protein-protein complexes.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein-protein interactions lie at the heart of most cellular processes. Many experimental and computational studies aim to deepen our understanding of these interactions and improve our capacity to predict them. In this respect, the evolutionary perspective is most interesting, since the preservation of structure and function puts constraints on the evolution of proteins and their interactions. However, uncovering these constraints remains a challenge, and the description and detection of evolutionary signals in protein-protein interactions is currently a very active field of research. Here, we review recent works dissecting the mechanisms of protein-protein interaction evolution and exploring how to use evolutionary information to predict interactions, both at the global level of the interactome and at the detailed level of protein-protein interfaces. We first present to what extent protein-protein interactions are found to be conserved within interactomes and which properties can influence their conservation. We then discuss the evolutionary and co-evolutionary pressures applied on protein-protein interfaces. Finally, we describe how the computational prediction of interfaces can benefit from evolutionary inputs.
    Archives of Biochemistry and Biophysics 07/2014; · 3.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the molecular basis of protein function remains a central goal of biology, with the hope to elucidate the role of human genes in health and in disease, and to rationally design therapies through targeted molecular perturbations. We review here some of the computational techniques and resources available for characterizing a critical aspect of protein function - those mediated by protein-protein interactions (PPI). We describe several applications and recent successes of the Evolutionary Trace (ET) in identifying molecular events and shapes that underlie protein function and specificity in both eukaryotes and prokaryotes. ET is a part of analytical approaches based on the successes and failures of evolution that enable the rational control of PPI.
    Progress in Biophysics and Molecular Biology 05/2014; · 2.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ultrafiltration and HPLC were employed to assess binding rates between rat plasma protein and two active compounds with lipid-regulating properties (alisol B 23-acetate and alisol A 24-acetate) from Alismaorientale rhizomes (Alismatis Rhizoma), a traditional Chinese medicine. SDS-PAGE was used for the evaluation of the binding between the alisol acetates and Hb in plasma. The fluorescence spectroscopy and circular dichroism spectroscopy were also combined with molecular modeling to explore binding mechanisms between Hb and the alisol acetates under imitative physiological condition. The ultrafiltration results show that alisol B 23-acetate bound more strongly than alisol A 24-acetate to plasma protein. SDS-PAGE results may suggest that alisols bind to Hb in plasma. The spectroscopy results are consisting with the molecular modeling results, and they indicate that the differences in plasma protein binding strength between the two compounds may be related to their side chains. A folded side chain/parent ring bound more strongly to Hb than an open side chain/parent ring.
    Bioorganic & medicinal chemistry letters. 07/2014;

Full-text (3 Sources)

Available from
Jun 6, 2014