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. 2012;7(8):e42468.
doi: 10.1371/journal.pone.0042468. Epub 2012 Aug 3.

Computational Identification of Novel Amino-Acid Interactions in HIV Gag via Correlated Evolution

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Free PMC article

Computational Identification of Novel Amino-Acid Interactions in HIV Gag via Correlated Evolution

Olga V Kalinina et al. PLoS One. .
Free PMC article

Abstract

Pairs of amino acid positions that evolve in a correlated manner are proposed to play important roles in protein structure or function. Methods to detect them might fare better with families for which sequences of thousands of closely related homologs are available than families with only a few distant relatives. We applied co-evolution analysis to thousands of sequences of HIV Gag, finding that the most significantly co-evolving positions are proximal in the quaternary structures of the viral capsid. A reduction in infectivity caused by mutating one member of a significant pair could be rescued by a compensatory mutation of the other.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The location of the positions described in the text on Gag sequence and structure.
The top shows a linear representation of Gag domain structure, with positions numbered according to GAG_HV1B1. The three non-trivial co-evolving clusters are shown beneath the domain structure, as are the appropriate regions of the alignment for a sub-set of the sequences used. Sequences are labeled by their GenBank (gb) or EMBL (emb) accession codes. The structures on the bottom right show where the positions in the figure lie on the known three-dimensional structures of Gag domains. The two most significant pairs are marked in the alignment.
Figure 2
Figure 2. Spatial arrangement of the two top-scoring pairs in a side view of the hexameric unit-cell of the mature capsid lattice (PDB ID 3mge).
A top view is shown in the top-right inset. The left insets highlight the top-scoring pairs of residues, which are shown in the sticks representation (yellow carbons). The side chain of 343L, which has previously been demonstrated to be crucial for formation of the mature lattice, is also shown (blue carbons).
Figure 3
Figure 3. The effect of changes in the most significant co-evolving pair on virus infectivity.
The reduction in infectivity caused by the single mutation is rescued by the compensatory mutation in the co-evolving residue.

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Grant support

H-GK and JAGB and were supported by a grant from the Deutsche Forschungsgemeinschaft within SPP 1175. OVK was partially supported by an EMBO Long Term Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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