Use of Molecular Dynamics in the Design and Structure Determination of a Photoinducible -Hairpin
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- 作者：Vincent Krä ; utler ; Andreas Aemissegger ; Philippe H. Hü ; nenberger ; Donald Hilvert ; Tomas Hansson ; and Wilfred F. van Gunsteren
- 刊名：Journal of the American Chemical Society
- 出版年：2005
- 出版时间：April 6, 2005
- 年：2005
- 卷：127
- 期：13
- 页码：4935 - 4942
- 全文大小：460K
- 年卷期：v.127,no.13(April 6, 2005)
- ISSN：1520-5126
文摘
The study presented here consists of three parts. In the first, the ability of a set of differentlysubstituted diazobenzene-based linkers to act as photoswitchable 
-turn building blocks was assessed. A12-residue peptide known to form -hairpins was taken as the basis for the modeling process. The central(-turn) residue pair was successively replaced by six symmetrically ((o,o), (m,m), or (p,p)) substituted(aminomethyl/carboxymethyl or aminoethyl/carboxyethyl) diazobenzene derivatives leading to a set ofpeptides with a photoswitchable backbone conformation. The folding behavior of each peptide was theninvestigated by performing molecular dynamics simulations in water (4 ns) and in methanol (10 ns) atroom temperature. The simulations suggest that (o,o)- and (m,m)-substituted linkers with a single methylenespacer are significantly better suited to act as photoswitchable -turn building blocks than the other linkersexamined in this study. The peptide containing the (m,m)-substituted linker was synthesized andcharacterized by NMR in its cis configuration. In the second part of this study, the structure of this peptidewas refined using explicit-solvent simulations and NOE distance restraints, employing a variety of refinementprotocols (instantaneous and time-averaged restraining as well as unrestrained simulations). We showthat for this type of systems, even short simulations provide a significant improvement in our understandingof their structure if physically meaningful force fields are employed. In the third part, unrestrained explicit-solvent simulations starting from either the NMR model structure (75 ns) or a fully extended structure(25 ns) are shown to converge to a stable -hairpin. The resulting ensemble is in good agreement withexperimental data, indicating successful structure prediction of the investigated hairpin by classical explicit-solvent molecular dynamics simulations.
-turn building blocks was assessed. A12-residue peptide known to form -hairpins was taken as the basis for the modeling process. The central(-turn) residue pair was successively replaced by six symmetrically ((o,o), (m,m), or (p,p)) substituted(aminomethyl/carboxymethyl or aminoethyl/carboxyethyl) diazobenzene derivatives leading to a set ofpeptides with a photoswitchable backbone conformation. The folding behavior of each peptide was theninvestigated by performing molecular dynamics simulations in water (4 ns) and in methanol (10 ns) atroom temperature. The simulations suggest that (o,o)- and (m,m)-substituted linkers with a single methylenespacer are significantly better suited to act as photoswitchable -turn building blocks than the other linkersexamined in this study. The peptide containing the (m,m)-substituted linker was synthesized andcharacterized by NMR in its cis configuration. In the second part of this study, the structure of this peptidewas refined using explicit-solvent simulations and NOE distance restraints, employing a variety of refinementprotocols (instantaneous and time-averaged restraining as well as unrestrained simulations). We showthat for this type of systems, even short simulations provide a significant improvement in our understandingof their structure if physically meaningful force fields are employed. In the third part, unrestrained explicit-solvent simulations starting from either the NMR model structure (75 ns) or a fully extended structure(25 ns) are shown to converge to a stable -hairpin. The resulting ensemble is in good agreement withexperimental data, indicating successful structure prediction of the investigated hairpin by classical explicit-solvent molecular dynamics simulations.