Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Nov 2;8(11):9968-9979.
doi: 10.1021/acscatal.8b03563. Epub 2018 Sep 13.

Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination

Xin Cindy Yan  1 , Anthony J Metrano  1 , Michael J Robertson  1 , Nadia C Abascal  1 , Julian Tirado-Rives  1 , Scott J Miller  1 , William L Jorgensen  1
Affiliations

Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination

Xin Cindy Yan et al. ACS Catal. .

Abstract

It is widely accepted that structural rigidity is required to achieve high levels of asymmetric induction in catalytic, enantioselective reactions. This fundamental design principle often does not apply to highly selective catalytic peptides that often exhibit conformational heterogeneity. As a result, these complex systems are particularly challenging to study both experimentally and computationally. Herein, we utilize molecular dynamics simulations to investigate the role of conformational mobility on the reactivity and selectivity exhibited by a catalytic, β-turn-biased peptide in an atroposelective bromination reaction. By means of cluster analysis, multiple distinct conformers of the peptide and a catalyst-substrate complex were identified in the simulations, all of which were corroborated by experimental NMR measurements. The simulations also revealed that a shift in the conformational equilibrium of the peptidic catalyst occurs upon addition of substrate, and the degree of change varies among different substrates. On the basis of these data, we propose a correlation between the composition of the peptide conformational ensemble and its catalytic properties. Moreover, these findings highlight the importance of conformational dynamics in catalytic, asymmetric reactions mediated by oligopeptides, unveiled through high-level, state-of-the-art computational modeling.

Keywords: Asymmetric Catalysis; Atropisomerism; Cluster Analysis; Conformation; Molecular Dynamics; Peptides.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Three distinct conformers of peptide 3 observed in crystal structures. Based on the ϕ and ψ dihedrals of the loop region residues and the internal H-bonding network, conformers 3a and 3b are classified as type II′ β-hairpins. Conformer 3c classifies as a type I′ β-turn that is pre-helical in geometry.
Figure 2.
Figure 2.
Joint distribution plots of backbone dihedral angles ϕ and ψ in the (a) i+1 and (b) i+2 residues of peptide 3 from MD simulations in benzene. The crystallographic values are marked by triangles.
Figure 3.
Figure 3.
Representative structures of the confonners identified from the cluster analysis: (a) Conformer 3a/b, (b) overlay of confonners 3c (blue) and 3d (green), and (c) confonner 3e.
Figure 4.
Figure 4.
Scatter plots of backbone dihedral angles ϕ and ψ in the (a) i+1 and (b) i+2 residues of peptide 3 from MD simulations in benzene (colored according to cluster). The crystallographic values and centroids of clusters are denoted by red triangles and black dots, respectively.
Figure 5.
Figure 5.
Conformational composition from cluster analysis. (a) Peptide 3 alone in benzene. (b) Peptide 3 in the presence of substrate (aS)-1a. (c) Peptide 3 in the presence of substrate (aS)-1b. (d) Peptide 3 in the presence of substrate (aR)-1a. (e) Peptide 3 in the presence of substrate (aR)-1b.
Figure 6.
Figure 6.
Joint distribution plots of backbone dihedral angles ϕ and ψ in the (a) i+1 and (b) i+2 residues of peptide 3 in the presence of substrate (aS)-1a from MD simulations in benzene. The crystallographic values are marked by triangles.
Figure 7.
Figure 7.
Composition of binding poses in the cluster analysis of (a) 3+1a complex and (b) 3+1b complex. (c) Overlay of binding pose A in the 3+1a (grey) and 3+1b (cyan) complexes.
Figure 8.
Figure 8.
Joint distribution plots of backbone dihedral angles ϕ and ψ in the (a) i+1 and (b) i+2 residues of peptide 3+1b from MD simulations in benzene. The crystallographic values are marked by triangles.
Figure 9.
Figure 9.
Plot of through-space distances from NOESY measurements versus simulations, (a) Intramolecular interactions in peptide 3. (b) Intennolecular interactions between peptide 3 and substrates in binding pose A.
Scheme 1.
Scheme 1.
Peptide-catalyzed, atroposelective bromination of 3-arylquinazolin-4(3H)-ones 1.
See this image and copyright information in PMC

References

    1. Knowles JR Enzyme Catalysis: Not Different, Just Better. Nature 1991, 350, 121–124. - PubMed
    2. Kirby AJ Enzyme Mechanisms, Models, and Mimics. Angew. Chem. Int. Ed 1996, 35, 706–724.
    3. Zhang X; Houk KN Why Enzymes are Proficient Catalysts: Beyond the Pauling Paradigm. Acc. Chem. Res 2005, 38, 379–385. - PubMed
    4. Smith AJT; Müller R; Toscano MD; Kast P; Hellinga HW; Hilvert D; Houk KN Structural Reorganization and Preorganization in Enzyme Active Sites: Comparisons of Experimental and Theoretically Ideal Active Site Geometries in the Multistep Serine Esterase Reaction Cycle. J. Am. Chem. Soc 2008, 130, 15361–15373. - PMC - PubMed
    1. For reviews, see: Miller SJ In Search of Peptide-Based Catalysts for Asymmetric Organic Synthesis. Acc. Chem. Res 2004, 37, 601–610. - PubMed
    2. Colby Davie EA; Mennen SM; Xu Y; Miller SJ Asymmetric Catalysis Mediated by Synthetic Peptides. Chem. Rev 2007, 107, 5759–5812. - PubMed
    3. Wennemers H Asymmetric Catalysis with Peptides. Chem. Commun 2011, 47, 12036–12041. - PubMed
    4. Lewandowski B Wennemers, H. Asymmetric Catalysis with Short-Chain Peptides. Curr. Opin. Chem. Biol 2014, 22, 40–46. - PubMed
    1. Doyle AG; Jacobsen EN Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev 2007, 107, 5713–5743. - PubMed
    2. Knowles RR; Jacobsen EN Attractive Noncovalent Interactions in Asymmetric Catalysis: Links Between Enzymes and Small Molecule Catalysts. Proc. Natl. Acad. Sci. U.S.A 2010, 107, 20678–20685. - PMC - PubMed
    3. Toste FD; Sigman MS; Miller SJ Pursuit of Noncovalent Interactions for Strategic Site-Selective Catalysis. Acc. Chem. Res 2017, 50, 609–615. - PMC - PubMed
    4. Davis HJ; Phipps RJ Harnessing Non-Covalent Interactions to Exert Control Over Regioselectivity and Site-Selectivity in Catalytic Reactions. Chem. Sci 2017, 8, 864–877. - PMC - PubMed
    1. For reviews on site-selective catalysis, see: Giuliano MW; Miller SJ Site-Selective Reactions with Peptide-Based Catalysts. Top. Curr. Chem 2016, 372, 157–201. - PubMed
    2. Shugrue CR; Miller SJ Applications of Non-Enzymatic Catalysts to the Alteration of Natural Products. Chem. Rev 2017, 117, 11894–11951. - PMC - PubMed
    3. Hartwig JF Catalyst-Controlled Site-Selective Bond Activation. Acc. Chem. Res 2017, 50, 549–555. - PMC - PubMed
    4. Huang Z; Dong G Site-Selectivity Control in Organic Reactions: A Quest to Differentiate Reactivity Among the Same Kind of Functional Group. Acc. Chem. Res 2017, 50, 465–471. - PubMed
    1. For select examples, see: Romney DK; Colvin SM; Miller SJ Catalyst Control over Regio- and Enantioselectivity in Baeyer-Villiger Oxidations of Functionalized Ketones. J. Am. Chem. Soc 2014, 136, 14019–14022. - PMC - PubMed
    2. Alford JS; Abascal NC; Shugrue CR; Colvin SM; Romney DK; Miller SJ Aspartyl Oxidation Catalysts that Dial in Functional Group Selectivity, along with Regio- and Stereoselectivity. ACS Cent. Sci 2016, 2, 733–739. - PMC - PubMed