Homology Modeling of Distant Lipocalin Homologs Using a Structure-based Fingerprint as a Constraint for Sequence Alignment

Abstract

The incessant expansion of protein sequence data presents a huge challenge in the identification of their structures which relies on laborious and time-consuming experimental approaches. Homology modeling of protein structure is highly accepted as an alternative to experimental approach, but its efficacy tends to decline when the sequence homology between the target and template sequences is low due to the limitation of their sequence alignment. Here, we demonstrated that employing a structure-based fingerprint of a homologous protein set as a constraint for the alignment of distant template and target sequences could improve the efficiency of homology modeling by using lipocalin proteins as a model system. Nine distantly related kernel lipocalins were structurally aligned, which was used to design a structure-based fingerprint consisting of commonly conserved hydrophobic and hydrophilic residues. The fingerprint was introduced as constraint in the alignment of template and target lipocalins, and the homology modeling of target lipocalin was performed based on the aligned sequences. Although the efficiency was marginal, the approach showed a consistent improvement compared to the homology modeling of lipocalin structures without the constraint for sequence alignment.