Disordered proteins and network disorder in network descriptions of protein structure, dynamics and function. Hypotheses and a comprehensive review

Abstract

During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into 'cumulus-type', i.e., those similar to puffy (white) clouds, and 'stratus-type', i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an 'energy transfer' mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by 'multi-trajectories'; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach 'rarely visited' but functionally-related states. We also show the role of disorder in 'spatial games' of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks. # Mr. Zsolt Hoksza is a high school student of the Fazekas High School (www.fazekas.hu) in Budapest, Hungary, who started his research as a member of the EU Descartes Award winning High School Research Student organization (www.kutdiak.hu) founded by P.C. and offering research opportunities for several thousands of high school students since 1996. STRUCTURE AND DYNAMICS OF PROTEINS AS NETWORKS 2.A. Definition of protein structure networks.Protein structure networks (also called protein contact networks) form the basal layer of the cellular network hierarchy. At the residue level of coarse-graining, the nodes are amino acids, while links connect amino acids whose inter-distance is below a cut-off (usually 0.4 to 0.85 nm) in the native fold. Protein structure networks may have weighted links instead of distance cut-offs, and may discriminate between individual atoms (like αC or βC atoms). Covalent bonds may be included or excluded in the network representation [1-9].2.B. Key topological properties of protein structure networks. In the small world of protein structure networks any two amino acids are separated by only a few links, and the network diameter grows logarithmically with increasing number of amino acids. This smallworldness promotes the fast transmission of perturbations (conformational changes). Typically, protein structure networks have a Poisson degree distribution rather than the widely characteristic scale-free degree distribution. This means that they have fewer hubs than expected, and amino acid "mega-hubs", having an extremely large number of neighbors do not exist, whic...

Heat Shock Partially Dissociates the Overlapping Modules of the Yeast Protein-Protein Interaction Network: A Systems Level Model of Adaptation

“…In former studies ‘stratus’ and ‘cumulus’ forms were described as alternative structures of the general form of yeast interactome [30]. Stratus- and cumulus-type organizations may be differing topology classes in many types of networks, such as in protein structure networks as we proposed recently [31].…”

Structure and dynamics of molecular networks: A novel paradigm of drug discovery

“…Distances are usually measured between Cα or Cβ atoms, but in some representations the centers of mass of the side chains are calculated, and distances are measured between them. Edges of unweighted protein structure networks connect amino acids having a distance below a cut-off distance, which is usually between 4 to 8.5 Å (Artymiuk et al, 1990; Kannan & Vishveshwara, 1999; Green & Higman, 2003; Bagler & Sinha, 2005; Böde et al, 2007; Krishnan et al, 2008; Vishveshwara et al, 2009; Doncheva et al, 2011; Csermely et al, 2012; Doncheva et al, 2012b; Di Paola et al, 2013). A detailed study compared the effect of various Cα-Cα contact assessments, such as the atom distance criteria, the isotropic sphere chain and the anisotropic ellipsoid side-chain models, as well as of the selection of various cut-off distances.…”

“…The best amino acid pair specific cut-off distances varied between 3.9 and 6.5 Å (Sun & He, 2011). In protein structure networks with weighted edges, edge weight is usually inversely proportional to the distance between the two amino acid side-chains (Artymiuk et al, 1990; Kannan & Vishveshwara, 1999; Green & Higman, 2003; Bagler & Sinha, 2005; Böde et al, 2007; Krishnan et al, 2008; Vishveshwara et al, 2009; Doncheva et al, 2011; Csermely et al, 2012; Doncheva et al, 2012b; Di Paola et al, 2013). …”

“…In protein structure networks we may find considerably less large hubs than in other networks. However, the existing smaller hubs still play an important role in protein structures, since these ‘micro-hubs’ were shown to increase the thermodynamic stability of proteins (Kannan & Vishveshwara, 1999; Green & Higman, 2003; Atilgan et al, 2004; Bagler & Sinha, 2005; Brinda & Vishveshwara, 2005; Del Sol et al, 2006; Alves & Martinez, 2007; Del Sol et al, 2007; Krishnan et al, 2008; Konrat, 2009; Morita & Takano, 2009; Estrada, 2010; Csermely et al, 2012). Protein structure networks possess a rich club structure with the exception of membrane proteins, where hubs form disconnected, multiple clusters (Pabuwal & Li, 2009).…”

“…Disordered protein regions serve the need for large flexibility, and therefore are often used, especially in the human proteome (Csermely et al, 2012; Tompa, 2012). Protein structure network description may be a useful method to describe the complexity of protein structures, which are neither very rigid, nor very flexible.…”