**1. Introduction**

Mutual synergistic folding (MSF) complexes are a unique subset of intrinsically disordered proteins (IDPs). MSF IDPs can adopt a stable structure during the interaction, without a pre-existing folded partner [1–4]. At the time of the mutual synergistic folding process, the participating IDPs of these complexes synergistically fold into a stable, globular complex. Demarest et al. (2002) investigated the first MSF interaction between the p160 transcriptional coactivator protein ACTR and the tumor suppressor CBP proteins. They found that this MSF complex contains many hydrophobic side-chains and highly specific intermolecular hydrogen bonds, as well as buried intermolecular salt bridges, which help to fold the complex [5]. Since IDPs often have a high net charge, and they have a small content of hydrophobic residues, they are usually not able to form a hydrophobic core [6]. However, MSF complexes contain more hydrophobic residues, presenting an exception to a general view of IDPs [7,8].

While IDPs mostly have low sequence complexity, MSF complexes are rather heterogeneous, like globular proteins. Furthermore, MSF proteinsare also heterogeneous in amino acid composition similar to globular proteins [8]. The residue-based disorder prediction methods, developed for identifying segments bound to folded proteins, cannot be used for detecting of MSF complexes. Systematic analyses are required to understand and predict these MSF interactions. Nevertheless, this is difficult to implement since a severe weakness of the literature is the little information available about these complexes. At present, the most comprehensive and systematic catalog of MSF complexes is the MFIB (Mutual Folding Induced by Binding) database containing 205 entries [9].

A protein in aqueous solution is only stable when it contains a hydrophobic core buried from water by polar residues. Furthermore, these polar residues shield most of the hydrophobic residues from the solvent. For the first criterion, the protein should contain more residues than a required minimum either as a monomer or as an oligomer. The fulfillment of the second criterion depends on the ratio of the polar and hydrophobic residues because the ratio of the surface and buried residues rapidly decreases by increasing the total number of residues. For a given hydrophilic/hydrophobic ratio, either a long polypeptide chain or oligomerization is needed. MSF proteins fulfill both criteria by oligomerization.

Recently, the physical background of homodimeric MSF complexes from MFIB [7] was analyzed. We identified the residues with solvent accessible main-chain patches (RSAMPs) and studied the "under-wrapped" hydrogen bonds (dehydrons), which are not shielded well enough from solvent [10]. Our results suggested that homodimeric MSF complexes contain more RSAMPs and dehydrons than homodimeric complexes where all the interacting chains are globular in their monomeric form. These properties should contribute to their disordered nature in monomeric form and to their folding in the oligomeric state. In this study, the role of this phenomenon for heterodimeric MSF complexes will be discussed. In the case of heterodimers, the interacting polypeptide chains have different amino acid compositions, which discriminates heterodimers from homodimers. The MFIB database contains, unfortunately, a much lower number of heterodimeric structures when compared to homodimeric ones. Furthermore, there are highly similar proteins among them, which makes redundancy filtering necessary.
