Flexible protein alignment and hinge detection

Abstract

Here we present a novel technique for the alignment of flexible proteins. The method does not require an a priori knowledge of the flexible hinge regions. The FlexProt algorithm simultaneously detects the hinge regions and aligns the rigid subparts of the molecules. Our technique is not sensitive to insertions and deletions. Numerous methods have been developed to solve rigid structural comparisons. Unlike FlexProt, all previously developed methods designed to solve the protein flexible alignment require an a priori knowledge of the hinge regions. The FlexProt method is based on 3-D pattern-matching algorithms combined with graph theoretic techniques. The algorithm is highly efficient. For example, it performs a structural comparison of a pair of proteins with 300 amino acids in about 7 s on a 400-MHz desktop PC. We provide experimental results obtained with this algorithm. First, we flexibly align pairs of proteins taken from the database of motions. These are extended by taking additional proteins from the same SCOP family. Next, we present some of the results obtained from exhaustive all-against-all flexible structural comparisons of 1329 SCOP family representatives. Our results include relatively high-scoring flexible structural alignments between the C-terminal merozoite surface protein vs. tissue factor; class II aminoacyl-tRNA synthase, histocompatibility antigen vs. neonatal FC receptor; tyrosine-protein kinase C-SRC vs. haematopoetic cell kinase (HCK); tyrosine-protein kinase C-SRC vs. titine protein (autoinhibited serine kinase domain); and tissue factor vs. hormone-binding protein. These are illustrated and discussed, showing the capabilities of this structural alignment algorithm, which allows un-predefined hinge-based motions.

A method for simultaneous alignment of multiple protein structures

“…A natural extension of multiple structural alignment is a Flexible Multiple Structural Alignment, where proteins are allowed to undergo hinge bending movements. 23 This work is now in progress.…”

“…5,7 In our method we use an algorithm which detects structurally similar fragments of maximal length, i.e., fragment pairs which cannot be extended while preserving ⑀-congruence. 19,23 For any multiple alignment problem we can always assume that the selected pivot molecule has to participate in all the alignments. If all the molecules are iteratively selected as pivots, then all solutions can be detected.…”

StoneHinge: Hinge prediction by network analysis of individual protein structures

“…Hinge detectors, such as FlexProt, 11 require two conformations of the protein and analyze which residues stay mutually rigid between the conformers or change in conformation; the latter are identified as hinges. On the other hand, hinge predictors such as the StoneHinge algorithms presented here identify the locations of hinges given a single structure as input.…”

“…11,32 FlexProt requires both the open and closed conformations of the protein as input, and the hinges are identified as the pair of residues bordering adjacent rigid fragments. The hinge assignments were made using default settings: a maximum of 3.0 Å RMSD between matched fragments in the two structures and a minimum size of 15 amino acids for matched fragments.…”

“…9,10 For instance, a twelve-residue, straplike hinge connects domains in the LAO binding protein. 8 Other hinge-prediction methods such as FlexProt 11 and StoneHingeD (presented here) define hinges as pivot points between two consecutive residues. StoneHingeD defines each hinge as a fixed point between connected regions undergoing large-scale opening and closing modes in DomDecomp.…”