Neutral (G.GC, A.AT, G.AT, T.AT, and C(imino).GC) and protonated (CH+.GC and AH+.GC) hydrogen-bonded trimers of nucleic acid bases were characterized by ab initio methods with the inclusion of electron correlation. In addition, the influence of metal cations on the third-strand binding in Purine-Purine-Pyrimidine (Pu.PuPy) reverse-Hoogsteen triplets has been studied. The ab initio calculations were compared with those from recently introduced force fields (AMBER4.1, CHARMM23, and CFF95). The three-body term in neutral trimers is mostly negligible, and the use of empirical potentials is justified. The only exception is the neutral G.GC Hoogsteen trimer with a three-body term of -4 kcal/mol. Protonated trimers are stabilized by molecular ion-molecular dipole attraction and the interaction within the complex is nonadditive, with the three-body term on the order of -3 kcal/mol. There is a significant induction interaction between the third-strand protonated base and guanine. The calculations indicate an enhancement of the third-strand binding in the G.GC reverse-Hoogsteen trimer due to-metal cation coordination to the N7/O6 position of the third-strand guanine. Interactions between metal cations and complexes of DNA bases are in general highly non-additive; the three-body term is above-10 kcal/mol in a complex of a divalent cation (Ca2+) with the GG reverse-Hoogsteen pair. The pairwise additive empirical potentials qualitatively underestimate the binding energy between cation and base.
Therapeutic peptides offer potential advantages over small molecules in terms of selectivity, affinity, and their ability to target "undruggable" proteins that are associated with a wide range of pathologies. Despite their importance, current molecular design capabilities that inform medicinal chemistry decisions on peptide programs are limited. More specifically, there are unmet needs for structure−activity relationship (SAR) analysis and visualization of linear, cyclic, and cross-linked peptides containing nonnatural motifs, which are widely used in drug discovery. To bridge this gap, we developed PepSeA (Peptide Sequence Alignment and Visualization), an open-source, freely available package of sequence-based tools (https://github.com/Merck/PepSeA). PepSeA enables multiple sequence alignment of non-natural amino acids and enhanced visualization with the hierarchical editing language for macromolecules (HELM). Via stepwise SAR analysis of a ChEMBL peptide data set, we demonstrate the utility of PepSeA to accelerate decision making in lead optimization campaigns in pharmaceutical setting. PepSeA represents an initial attempt to expand cheminformatics capabilities for therapeutic peptides and to enable rapid and more efficient design-make-test cycles.
Protein engineering
is the discipline of developing useful proteins
for applications in research, therapeutic, and industrial processes
by modification of naturally occurring proteins or by invention of de novo proteins. Modern protein engineering relies on the
ability to rapidly generate and screen diverse libraries of mutant
proteins. However, design of mutant libraries is typically hampered
by scale and complexity, necessitating development of advanced automation
and optimization tools that can improve efficiency and accuracy. At
present, automated library design tools are functionally limited or
not freely available. To address these issues, we developed Mutation
Maker, an open source mutagenic oligo design software for large-scale
protein engineering experiments. Mutation Maker is not only specifically
tailored to multisite random and directed mutagenesis protocols, but
also pioneers bespoke mutagenic oligo design for de novo gene synthesis workflows. Enabled by a novel bundle of orchestrated
heuristics, optimization, constraint-satisfaction and backtracking
algorithms, Mutation Maker offers a versatile toolbox for gene diversification
design at industrial scale. Supported by in silico simulations and compelling experimental validation data, Mutation
Maker oligos produce diverse gene libraries at high success rates
irrespective of genes or vectors used. Finally, Mutation Maker was
created as an extensible platform on the notion that directed evolution
techniques will continue to evolve and revolutionize current and future-oriented
applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.