Multiple mapping method: A novel approach to the sequence‐to‐structure alignment problem in comparative protein structure modeling

Abstract

A major bottleneck in comparative protein structure modeling is the quality of input alignment between the target sequence and the template structure. A number of alignment methods are available, but none of these techniques produce consistently good solutions for all cases. Alignments produced by alternative methods may be superior in certain segments but inferior in others when compared to each other; therefore, an accurate solution often requires an optimal combination of them. To address this problem, we have developed a new approach, Multiple Mapping Method (MMM). The algorithm first identifies the alternatively aligned regions from a set of input alignments. These alternatively aligned segments are scored using a composite scoring function, which determines their fitness within the structural environment of the template. The best scoring regions from a set of alternative segments are combined with the core part of the alignments to produce the final MMM alignment. The algorithm was tested on a dataset of 1400 protein pairs using 11 combinations of two to four alignment methods. In all cases MMM showed statistically significant improvement by reducing alignment errors in the range of 3 to 17%. MMM also compared favorably over two alignment meta-servers. The algorithm is computationally efficient; therefore, it is a suitable tool for genome scale modeling studies.

Identification of Linear Epitopes in Bacillus anthracis Protective Antigen Bound by Neutralizing Antibodies

“…Molecular Modeling-Comparative protein structure models were generated for mAbs 7.5G and 19D9 based on the available similar structures of IgG2b and IgG1 molecules, respectively (Protein Data Bank accession codes 1ibg and 3dvg), using the multiple mapping method (20) to generate a targettemplate sequence alignment and MODELLER (21) to generate the atomic models. mAbs 7.5G and 19D9 share 42 and 41% identical positions with 1ibg and 3dvg template structures, respectively.…”

“…The amounts of digested products, PA 20 and PA 63 , increased in the absence of mAb 19D9, whereas the amount of undigested PA 83 decreased over time. At all time intervals, there were less PA 20 and PA 63 and more PA 83 when mAb 19D9 was present. Hence, mAb 19D9 significantly slows the proteolytic cleavage of PA 83 to PA 20 and PA 63 .…”

“…The cellular receptor binding region is localized to the small loop of domain 4, and this region has been described to be recognized by two neutralizing mAbs (7,9). With the exception of a neutralizing mAb that bound to PA 20 (13), no B-cell epitopes have been reported in domain 1. Therefore, identification of further dominant antigenic epitopes is pivotal for understanding the minimal immunogenic region of PA that will allow for precise direction of potent immune responses.…”

“…Cleavage of PA and Dissociation of PA 20 -To examine whether mAb 19D9 binding affects dissociation of PA 20 from PA 63 , PA was digested with 2 units of furin for 1-, 3-, 5-, and 10 -12-min intervals in the presence and absence of mAb. PA 83 and its digested products were separated on a 12% SDS-PAGE (Fig.…”

3D model of amphioxus steroid receptor complexed with estradiol

“…arginine/lysine, glutamic acid/aspartic acid], after addition of gaps [ Figure 1]. We used the Multiple Mapping Method (MMM) software [22] to construct the 3D model of amphioxus SR. Five alignment algorithms Muscle, Align2D, T-Coffee, ClustalW and ClustalW with modified gap penalty were used to align the target sequence, amphioxus SR [GenBank: ACB10649], with the human ERα template. MMM took each alignment and constructed a composite alignment, which was used by Modeller [23] to construct a 3D model of amphioxus SR.…”