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. 2015 Oct 16;2(Pt 6):643-52.
doi: 10.1107/S2052252515015250. eCollection 2015 Nov 1.

Changes in Protein Structure at the Interface Accompanying Complex Formation

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Free PMC article

Changes in Protein Structure at the Interface Accompanying Complex Formation

Devlina Chakravarty et al. IUCrJ. .
Free PMC article

Abstract

Protein interactions are essential in all biological processes. The changes brought about in the structure when a free component forms a complex with another molecule need to be characterized for a proper understanding of molecular recognition as well as for the successful implementation of docking algorithms. Here, unbound (U) and bound (B) forms of protein structures from the Protein-Protein Interaction Affinity Database are compared in order to enumerate the changes that occur at the interface atoms/residues in terms of the solvent-accessible surface area (ASA), secondary structure, temperature factors (B factors) and disorder-to-order transitions. It is found that the interface atoms optimize contacts with the atoms in the partner protein, which leads to an increase in their ASA in the bound interface in the majority (69%) of the proteins when compared with the unbound interface, and this is independent of the root-mean-square deviation between the U and B forms. Changes in secondary structure during the transition indicate a likely extension of helices and strands at the expense of turns and coils. A reduction in flexibility during complex formation is reflected in the decrease in B factors of the interface residues on going from the U form to the B form. There is, however, no distinction in flexibility between the interface and the surface in the monomeric structure, thereby highlighting the potential problem of using B factors for the prediction of binding sites in the unbound form for docking another protein. 16% of the proteins have missing (disordered) residues in the U form which are observed (ordered) in the B form, mostly with an irregular conformation; the data set also shows differences in the composition of interface and non-interface residues in the disordered polypeptide segments as well as differences in their surface burial.

Keywords: bioinformatics; bound and unbound protein forms; crystallographic temperature factor; disorder–order transition; interface area; molecular recognition; protein flexibility; protein–protein interactions; secondary structure.

Figures

Figure 1
Figure 1
Hydrogen-bond geometries (distances shown) in α-amylase (green) and tendamistat (cyan) between His201 NE2 and Tyr820 OH for (a) the pseudo-complex and (b) the experimental complex [PDB entry 1bvn (Wiegand et al., 1995 ▸); PDB entries 1pig (Machius et al., 1996 ▸) and 1hoe (Pflugrath et al., 1986 ▸) are the U forms]. ΔASA for the participating atom and all of the interface atoms of the residues are −0.6 and −3.2 Å2, respectively, for His, and 4.2 and 15.5 Å2, respectively, for Tyr.
Figure 2
Figure 2
The complex between the core domain of HspBP1 and the Hsp70 ATPase domain, an example of the change in the position of interface residues (stick representation; red in the B form and blue in the U form). Protein chains are shown in cartoon representation in green for the B form (PDB entry 1xqs) and in pink for the U form (PDB entry 1xqr) of the core domain of HspBP1 (Shomura et al., 2005 ▸) containing the labelled interface residues; the other component (the Hsp70 ATPase domain) in the B form is shown in cyan. ΔASA = −175 Å2 and δA = −10%. The ΔASA values for the interface atoms of the residues shown are −43 Å2 for Arg217, −20 Å2 for Glu218 and −16 Å2 for Phe210.
Figure 3
Figure 3
Plot of ΔASA of the interface atoms separated into the two components for each complex. The greater of the two values is labelled ΔASA2 and the lesser ΔASA1.
Figure 4
Figure 4
Secondary-structural changes during the U-to-B transition. (a) The change in percentage composition between the two states (B – U) for the secondary-structural elements (helix, H; strand, S; turn, T; irregular, C) for the cases with Euclidean distances between the two sets of compositions of >5. (b) Percentage composition of 224 residues showing the C/T to H/S transition, categorized into the extension of an already existing helix/strand (EH and ES) or the formation of a new helix/strand (FH and FS).
Figure 5
Figure 5
Examples showing changes in secondary-structural elements (left panel, U; right panel, B). Stretches in the interface are in yellow. (a) Amicyanin (PDB entry 2rac; Zhu et al., 1998 ▸) in complex (PDB entry 2mta; Chen et al., 1994 ▸) with methylamine dehydrogenase exhibits the formation of two antiparallel β-strands (Pro52, Asn54, His56 and Val58 in one, and Lys68, Gly69, Pro70, Met71 and Lys73 in the other) and N-terminal (Arg99) and C-terminal (His91) extension of two other strands. (b) Metalloproteinase inhibitor 1 (PDB entry 1d2b; Wu et al., 2000 ▸) in complex (PDB entry 2j0t; Iyer et al., 2006 ▸) with MMP1 intersitial collagenase displays the formation of a small helix (Glu67, Ser68, Val69 and Cys70) and C-terminal (Lys88) extension of a strand.
Figure 6
Figure 6
The structure of the interface formed in human tissue inhibitor of metalloproteinases 2 when it forms a complex with type IV collagenase (PDB entry 1gxd; Morgunova et al., 2002 ▸); the inhibitor is denoted in cyan and the enzyme in violet. Surface representations of the proteins are displayed. The U state (PDB entry 1br9; Tuuttila et al., 1998 ▸) is not shown here. The interface residues are split into two categories: the residues missing in the unbound structure are in blue and those seen in both the U and B forms are in orange. The missing segment (183–192) is composed of both non-interface residues (shown in red) and interface residues (blue). The missing residues contribute 504 Å2 to the BSA of 1268 Å2 of the inhibitor.
Figure 7
Figure 7
The loop (1–12) missing in the U form of neurotrophin-4 (PDB entry 1b98; Robinson et al., 1999; shown as green cartoon) which is present in the B form (PDB entry 1hcf; Banfield et al., 2001; cyan) on forming a complex with the BDNF/NT-3 growth factor receptor TrkB-d5 (magenta cartoon). The interface residues (in blue) are interspersed with non-interface residues (in red) in the missing loop. The contribution of the missing residues is 383 Å2 to the BSA of 765 Å2.
Figure 8
Figure 8
Euclidean distances involving B factors (a) between interface and surface regions (enumerated in Supplementary Table S3) and (b) between interface rim and core regions (Supplementary Table S4) in the U and B states.

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