Hot spot residue

Woods V.L. Jr Methods for identifying hot-spot residues of binding proteins and small compounds that bind to the same. U.S. Patent 6 599 707, 2003. 

In our simulations, we performed association studies to elucidate their role by selecting pairs of those hot spot residues that established a barnase-barstar contact in the bound complex. In these simulations, we studied what effect the side-chain conformation had on contact formation for certain hot spot residue pairs. A typical result is shown in Figure 8. Starting from the correct rotameric state for certain hot spot residue pairs with the rest of the proteins in their unbound conformations leads to improved contact formation in the initial docking phase. This effect is not observed when performing equivalent simulations with non-hot-spot interfacial residue pairs. 

Figure 8 The impact of hot-spot residue pair conformations on contact formation during docking of barnase (bn) and barstar (bs). Contact formation (as measured by the percentage of native contacts) during the first 100 ps of torsion dynamics simulations is shown see text for details.

A series of simulations starting from reverse initial conditions (protein structures in bound conformations with hot-spot residue pairs in unbound rotameric states) leads to impaired contact formation during the initial docking phase. These findings indicate, first, that the hot-spot residues can actively hinder or support contact formation and second, that a side-chain refinement protocol relying on specific side-chain rotameric states may well miss crucial structural detail in the interfacial region. 

There is another type of hot spot determination methods structure-based qualitative methods. The PP SITE method uses hydrogen bonds and hydrophobic characteristics to describe interactions between proteins and to decompose the contribution of atoms in hot spot residues.4 Hu et al derived another qualitative method recently based in the sequence and structure alignments proteins. Residues are characterized as hot spots based in their conserved, polar characteristics.98... 

Keskin O, Ma B, R Nussinov R (2005) Hot regions in protein-protein interactions the organization and contribution of structurally conserved hot spot residues, J Mol Biol, 345 1281—1294... 

The most common element of secondary structure in proteins is the helix. Helices are enriched at protein/protein interfaces, where a helixxleft motif is often employed to recognize hot spot residues at the protein/protein interface. Helices are also enriched in protein/nucleic acid interactions, where the helical motif facilitates molecular recognition by projecting residues into the grooves of nucleic acid helices. 

A study by Bullock et al. revealed that roughly 60% of helical interfaces in the HIPP dataset feature helices with hot spot residues on one face of the helix (Fig. 6b, d), a third of the complexes utilize helices with hot spots on two faces (Fig. 6b, e), and roughly 10% require all three faces for interaction with the target protein partner (Fig. 6b, f). The full list of PPIs that correspond to each category is published elsewhere [67]. Overall percent occurrences of hot spot residues at the first 12 positions in interfacial helices are depicted in Fig. 6c. The results of the study indicate that helix surface mimetics may prove to be a highly effective class of synthetic... 

Fig. 6 Energetic contributions of residues on different faces of interfacial helices, (a) Positioning of side-chain residues on a canonical a-helix, (b) percent occurrence of hot spot residues on one, two, or three helical faces (total number helices in each category shown in parentheses), (c) percent occurrence of hot spot residues as a function of helix position, (d-f) examples of protein complexes with hot spot residues on one face, two faces, and three faces (PDB codes 1x13, lxiu, and lor7) (Adapted with permission from Bullock et al. [67], Copyright (2011) American Chemical Society)...

Fig. 11 Classification of contact residues on partner proteins. Residues on the partner protein that are within 5 A of the helical hot spot residue were analyzed within Rosetta (Reprinted with permission from Bullock et al. [67], Copyright (2011) American Chemical Society)...

Hydrophobic and aromatic residues constitute a majority of hot spot residues however, polar and charged residues are also significant contributors at interfaces (Fig. 9b) [90]. This analysis supports the common perception that PPIs are generally hydrophobic but also feature key polar interactions that appreciably influence the binding energy landscape [28]. This view is further supported by the evaluation of residues on the partner protein that are within 5 A of the helical hot spot residue (Fig. 11). Not surprisingly a majority of residues that are within the specified radius of a hydrophobic residue are themselves hydrophobic, which is consistent with the... 

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