Limits...
Building on Cram's legacy: stimulated gating in hemicarcerands.

Liu F, Helgeson RC, Houk KN - Acc. Chem. Res. (2014)

Bottom Line: We found that the side portals of this hemicarceplex have multiple thermally accessible conformations.Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation.The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.

ABSTRACT
CONSPECTUS: Donald Cram's pioneering Nobel Prize-winning work on host-guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host-guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating. The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a "chair" to a "boat" structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating. We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

Show MeSH

Related in: MedlinePlus

(a) Ribbonstructure of pancreatic lipase (PDB entry 1HPL) with the activesite (shown in yellow) covered by the lid (shown in purple). (b) Ribbonstructures of HIV-1 protease in both closed (PDB entry 1TW7) and semiopen (PDBentry 2NPH)states (shown in blue and green, respectively).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4215849&req=5

fig1: (a) Ribbonstructure of pancreatic lipase (PDB entry 1HPL) with the activesite (shown in yellow) covered by the lid (shown in purple). (b) Ribbonstructures of HIV-1 protease in both closed (PDB entry 1TW7) and semiopen (PDBentry 2NPH)states (shown in blue and green, respectively).

Mentions: Many natural enzymes control access of substrates tothe activesites by the conformational changes of peptide loops; this phenomenonhas been referred to as “gating”.5 Pancreatic lipase, an enzyme that hydrolyzes dietary fatin the digestive system, has a lid over its active site when not activated(Figure 1a). The lid opens when the proteinis activated upon contact with a lipid surface. This conformationalchange was probed by EPR spectroscopy in a recent publication by Carrièreand co-workers.6 HIV-1 protease undergoesa sliding door mechanism (see later discussion), as revealed fromboth crystal structure analysis and molecular dynamics simulations.7 Figure 1b shows the overlapof HIV-1 protease in its semiopen (green) and closed (blue) conformations. In the closed conformation, the two flaps are packed onto each other closely,restricting access to the active site. In the semiopen conformation, the two flaps slide away from each other slightly.Molecular dynamics studies suggested that the flaps can separate evenfurther into an open conformation, in which the activesite is completely exposed to the environment. It is postulated thatthe gating motion from open to closed results from the presence ofthe ligand in the active site.7a


Building on Cram's legacy: stimulated gating in hemicarcerands.

Liu F, Helgeson RC, Houk KN - Acc. Chem. Res. (2014)

(a) Ribbonstructure of pancreatic lipase (PDB entry 1HPL) with the activesite (shown in yellow) covered by the lid (shown in purple). (b) Ribbonstructures of HIV-1 protease in both closed (PDB entry 1TW7) and semiopen (PDBentry 2NPH)states (shown in blue and green, respectively).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215849&req=5

fig1: (a) Ribbonstructure of pancreatic lipase (PDB entry 1HPL) with the activesite (shown in yellow) covered by the lid (shown in purple). (b) Ribbonstructures of HIV-1 protease in both closed (PDB entry 1TW7) and semiopen (PDBentry 2NPH)states (shown in blue and green, respectively).
Mentions: Many natural enzymes control access of substrates tothe activesites by the conformational changes of peptide loops; this phenomenonhas been referred to as “gating”.5 Pancreatic lipase, an enzyme that hydrolyzes dietary fatin the digestive system, has a lid over its active site when not activated(Figure 1a). The lid opens when the proteinis activated upon contact with a lipid surface. This conformationalchange was probed by EPR spectroscopy in a recent publication by Carrièreand co-workers.6 HIV-1 protease undergoesa sliding door mechanism (see later discussion), as revealed fromboth crystal structure analysis and molecular dynamics simulations.7 Figure 1b shows the overlapof HIV-1 protease in its semiopen (green) and closed (blue) conformations. In the closed conformation, the two flaps are packed onto each other closely,restricting access to the active site. In the semiopen conformation, the two flaps slide away from each other slightly.Molecular dynamics studies suggested that the flaps can separate evenfurther into an open conformation, in which the activesite is completely exposed to the environment. It is postulated thatthe gating motion from open to closed results from the presence ofthe ligand in the active site.7a

Bottom Line: We found that the side portals of this hemicarceplex have multiple thermally accessible conformations.Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation.The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.

ABSTRACT
CONSPECTUS: Donald Cram's pioneering Nobel Prize-winning work on host-guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host-guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating. The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a "chair" to a "boat" structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating. We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

Show MeSH
Related in: MedlinePlus