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Navigating complex peptide structures using macrocycle conformational maps.

ABSTRACT: Identification of turn motifs that are stabilized by intramolecular hydrogen bonds can be useful in describing the conformation of peptide systems. However, this approach is somewhat insufficient for cyclic peptides because peptide regions that are not positioned within a hydrogen bond can be left with no description. Furthermore, non-regular secondary structures and other rarely-observed conformations can be left without detailed evaluation. Herein, we describe "higher-order" ϕ/ψ plots termed macrocycle conformational maps (MCMs) as a tool for evaluating and comparing the conformations of a series of structurally related macrocyclic peptides.

SUBMITTER: McTiernan TJ

PROVIDER: S-EPMC9175111 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Navigating complex peptide structures using macrocycle conformational maps.

McTiernan Timothy J TJ Diaz Diego B DB Saunders George J GJ Sprang Fiona F Yudin Andrei K AK

RSC chemical biology 20220419 6

Identification of turn motifs that are stabilized by intramolecular hydrogen bonds can be useful in describing the conformation of peptide systems. However, this approach is somewhat insufficient for cyclic peptides because peptide regions that are not positioned within a hydrogen bond can be left with no description. Furthermore, non-regular secondary structures and other rarely-observed conformations can be left without detailed evaluation. Herein, we describe "higher-order" <i>ϕ</i>/<i>ψ</i> ...[more]

PMID: 35755184

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Project description:ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation.

Dataset Information

Navigating complex peptide structures using macrocycle conformational maps.

Publications

Navigating complex peptide structures using macrocycle conformational maps.

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