Structural informatics, modeling, and design with an open‐source Molecular Software Library (MSL)

Kulp, Daniel W.; Subramaniam, Sabareesh; Donald, Jason E.; Hannigan, Brett T.; Mueller, Benjamin K.; Grigoryan, Gevorg; Senes, Alessandro

doi:10.1002/jcc.22968

Cited by 24 publications

(39 citation statements)

References 48 publications

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“…In addition, a new biased glycan sampling program, GlycanTransfer, was written in MSL (42) to explore alternative glycan conformations capable of mimicking the interaction of the N332 glycan with PGT128. Brief details of the GlycanTransfer program are as follows.…”

Section: Methodsmentioning

confidence: 99%

Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV

et al. 2014

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Broadly neutralizing monoclonal antibodies (bnMAbs) that target the high-mannose patch centered around the glycan at position 332 on HIV Env are promising vaccine leads and therapeutic candidates as they effectively protect against mucosal SHIV challenge and strongly suppress SHIV viraemia in established infection in macaque models. However, these antibodies demonstrate varying degrees of dependency on the N332 glycan site and the origins of their neutralization breadth are not always obvious. By measuring neutralization on an extended range of glycan site viral variants, we found that some bnMAbs can utilize alternate N-linked glycans in the absence of the N332 glycan site and therefore neutralize a substantial number of viruses lacking the site. Furthermore, many of the antibodies can neutralize viruses in which the N332 glycan site is shifted to the 334 position. Finally, we found that a combination of three antibody families that target the high-mannose patch can lead to 99% neutralization coverage of a large panel of viruses containing the N332/334 glycan site and up to 66% coverage for viruses that lack the N332/334 glycan site. The results indicate that a diverse response against the high-mannose patch may provide near equivalent coverage as a combination of bnMAbs targeting multiple epitopes. Additionally, the ability of some bnMAbs to utilize other N-linked glycan sites can help counter neutralization escape mediated by shifting of glycosylation sites. Overall, this work highlights the importance of promiscuous glycan binding properties in bnMAbs to the high-mannose patch for optimal anti-viral activity either in protective or therapeutic modalities.

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Section: Methodsmentioning

confidence: 99%

Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV

et al. 2014

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“…All calculations were implemented and performed using the MSL molecular modeling libraries v. 1.1 (18), an open source C++ library that is freely available (19).…”

Section: Methodsmentioning

confidence: 99%

“…Energies were determined using the CHARMM 22 van der Waals function (34) and the hydrogen bonding function of SCWRL 4 (14), as implemented in MSL C++ libraries (18). Cα-H hydrogen bonds have been included as part of the energy functions of Rosetta Membrane (35).…”

Section: Methodsmentioning

confidence: 99%

“…Finally, all closely related solutions are clustered by similarity (RMSD < 2 Å), and the lowest-energy structure is reported as a representative model of its cluster. CATM is explained in full detail in Methods, and is freely available for download with MSL (18), a C++ open source macromolecular modeling software library (19).…”

Section: Gas Right Motifs Are Optimized For Cα-h Hydrogen Bond Networkmentioning

confidence: 99%

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A frequent, GxxxG-mediated, transmembrane association motif is optimized for the formation of interhelical Cα–H hydrogen bonds

Mueller

Subramaniam

Senes

2014

Proc. Natl. Acad. Sci. U.S.A.

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143

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Carbon hydrogen bonds between Cα-H donors and carbonyl acceptors are frequently observed between transmembrane helices (Cα-H···O=C). Networks of these interactions occur often at helix−helix interfaces mediated by GxxxG and similar patterns. Cα-H hydrogen bonds have been hypothesized to be important in membrane protein folding and association, but evidence that they are major determinants of helix association is still lacking. Here we present a comprehensive geometric analysis of homodimeric helices that demonstrates the existence of a single region in conformational space with high propensity for Cα-H···O=C hydrogen bond formation. This region corresponds to the most frequent motif for parallel dimers, GAS right , whose best-known example is glycophorin A. The finding suggests a causal link between the high frequency of occurrence of GAS right and its propensity for carbon hydrogen bond formation. Investigation of the sequence dependency of the motif determined that Gly residues are required at specific positions where only Gly can act as a donor with its "side chain" Hα. Gly also reduces the steric barrier for nonGly amino acids at other positions to act as Cα donors, promoting the formation of cooperative hydrogen bonding networks. These findings offer a structural rationale for the occurrence of GxxxG patterns at the GAS right interface. The analysis identified the conformational space and the sequence requirement of Cα-H···O=C mediated motifs; we took advantage of these results to develop a structural prediction method. The resulting program, CATM, predicts ab initio the known high-resolution structures of homodimeric GAS right motifs at near-atomic level.interaction motifs | protein prediction

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“…Support programs for MaDCaT (e.g. for building database and query maps and analysis of results) utilize the Molecular Software Library (MSL)(Kulp et al, 2012), freely available at http://msl-libraries.org. The web interface for MaDCaT is currently limited to searching over a sub-sample of the PDB, which does not find the best available matches to a motif, but in our experience can still be used to grossly estimate its designability.…”

Section: Madcatmentioning

confidence: 99%

Mining Tertiary Structural Motifs for Assessment of Designability

Zhang

Grigoryan

2013

Methods in Enzymology

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The observation of a limited secondary-structural alphabet in native proteins, with significant sequence preferences, has profoundly influenced the fields of protein design and structure prediction (Simons et al., 1997; Verschueren et al., 2011). In the era of structural genomics, as the size of the structural dataset continues to grow rapidly, it is becoming possible to extend this analysis to tertiary structural motifs and their sequences. For a hypothetical tertiary motif, the rate of its utilization in natural proteins may be used to assess its designability - the ease with which the motif can be realized with natural amino acids. This requires a structural similarity search methodology, which rather than looking for global topological agreement (more appropriate for functional categorization of proteins or domains), identifies detailed geometric matches. In this chapter we introduce such a method, called MaDCaT, and demonstrate its use by assessing the designability landscapes of two tertiary structural motifs. We also show that such analysis can establish structure/sequence links by providing the sequence constraints necessary to encode designable motifs. As a logical extension of their secondary-structure counterparts, statistics of tertiary structural preferences will likely prove extremely useful in de novo protein design and structure prediction.

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Structural informatics, modeling, and design with an open‐source Molecular Software Library (MSL)

Cited by 24 publications

References 48 publications

Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV

Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV

A frequent, GxxxG-mediated, transmembrane association motif is optimized for the formation of interhelical Cα–H hydrogen bonds

Mining Tertiary Structural Motifs for Assessment of Designability

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