Exploring the Energy Landscapes of Cyclic Tetrapeptides with Discrete Path Sampling

Cyclic tetrapeptides are an important class of biologically active molecules that exhibit interesting conformational dynamics, with slow interconversion of several different structures. We present calculations on their energy landscapes using discrete path sampling. In acyclic peptides and large cyclic peptides, isomers containing cis-peptide groups are much less stable than the all-trans isomers and separated from them by large barriers. Strain in small cyclic peptides causes the cis and trans isomers to be closer in energy and separated by much lower barriers. If d-amino acids or proline residues are introduced, isomers containing cis-peptides become more stable than the all-trans structures. We also show that changing the polarity of the solvent has a significant effect on the energy landscapes of cyclic tetrapeptides, causing changes in the orientations of the peptide groups and in the degree of intramolecular hydrogen bonding.

[1]  David J. Wales,et al.  Symmetrization of the AMBER and CHARMM force fields , 2010, J. Comput. Chem..

[2]  Matthew P Jacobson,et al.  Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. , 2006, Journal of the American Chemical Society.

[3]  Garland R Marshall,et al.  Engineering cyclic tetrapeptides containing chimeric amino acids as preferred reverse-turn scaffolds. , 2006, Journal of medicinal chemistry.

[4]  Eric J. Martin,et al.  Conformational Analysis of Macrocycles: Finding What Common Search Methods Miss , 2009, J. Chem. Inf. Model..

[5]  Juan R. Granja,et al.  Antibacterial agents based on the cyclic d,l-α-peptide architecture , 2001, Nature.

[6]  Lindsey J. Munro,et al.  DEFECT MIGRATION IN CRYSTALLINE SILICON , 1999 .

[7]  W. Lipscomb,et al.  Structure of cyclo(-L-prolylglycyl-)2 trihydrate. , 1989, Acta crystallographica. Section C, Crystal structure communications.

[8]  M. Karplus,et al.  The topology of multidimensional potential energy surfaces: Theory and application to peptide structure and kinetics , 1997 .

[9]  David J. Craik,et al.  Seamless Proteins Tie Up Their Loose Ends , 2006, Science.

[10]  M. Delaforge,et al.  Predicting the conformational states of cyclic tetrapeptides. , 2003, Biopolymers.

[11]  Tjerk P. Straatsma,et al.  NWChem: A comprehensive and scalable open-source solution for large scale molecular simulations , 2010, Comput. Phys. Commun..

[12]  Durba Sengupta,et al.  The molecular basis for antimicrobial activity of pore-forming cyclic peptides. , 2011, Biophysical journal.

[13]  Horst Kessler,et al.  Conformation and Biological Activity of Cyclic Peptides , 1982 .

[14]  Peter G. Schultz,et al.  Evolution of cyclic peptide protease inhibitors , 2011, Proceedings of the National Academy of Sciences.

[15]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[16]  H. Scheraga,et al.  Stability of cis, trans, and nonplanar peptide groups. , 1976, Macromolecules.

[17]  David J Wales,et al.  Finding pathways between distant local minima. , 2005, The Journal of chemical physics.

[18]  K. Wüthrich,et al.  1H- and 13C-NMR. Studies of the molecular conformations of cyclo-tetraglycyl [1] , 1975 .

[19]  Sergei V. Krivov,et al.  Free energy disconnectivity graphs: Application to peptide models , 2002 .

[20]  Rodrigo D. Tosso,et al.  Ab initio and DFT study of the conformational energy hypersurface of cyclic Gly-Gly-Gly. , 2009, The journal of physical chemistry. A.

[21]  D. Wales.  Discrete path sampling , 2002 .

[22]  M. Yoshida,et al.  Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. , 1993, The Journal of biological chemistry.

[23]  B. Reif,et al.  The conformation of cyclo(-D-Pro-Ala4-) as a model for cyclic pentapeptides of the DL4 type. , 2006, Journal of the American Chemical Society.

[24]  Horst Kessler,et al.  N-methylated cyclic RGD peptides as highly active and selective αvβ3 integrin antagonists , 1999 .

[25]  David J Wales,et al.  Interpolation schemes for peptide rearrangements. , 2010, The Journal of chemical physics.

[26]  David J Wales,et al.  Energy landscapes: some new horizons. , 2010, Current opinion in structural biology.

[27]  S. Gellman,et al.  Stereochemical Requirements for β-Hairpin Formation: Model Studies with Four-Residue Peptides and Depsipeptides , 1996 .

[28]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[29]  Hajime Okamoto,et al.  Conformational transitions of cyclic D,L‐peptides , 2009, J. Comput. Chem..

[30]  M. Zacharias,et al.  Reversible scaling of dihedral angle barriers during molecular dynamics to improve structure prediction of cyclic peptides. , 2004, The journal of peptide research : official journal of the American Peptide Society.

[31]  W. V. Philipsborn,et al.  Conformational Dependence of One‐Bond Cα,H Spin Coupling in Cyclic Peptides , 1981 .

[32]  J. Doye,et al.  Global Optimization by Basin-Hopping and the Lowest Energy Structures of Lennard-Jones Clusters Containing up to 110 Atoms , 1997, cond-mat/9803344.

[33]  É. Pinet,et al.  Multiple interconverting conformers of the cyclic tetrapeptide tentoxin, [cyclo‐(L‐MeAla1‐L‐Leu2‐MePhe[(Z)Δ]3‐Gly4)], as seen by two‐dimensional 1H‐nmr spectroscopy , 1995, Biopolymers.

[34]  E. Blout,et al.  Cyclic peptides. VIII. Carbon-13 and proton nuclear magnetic resonance evidence for slow cis'-trans' rotation in a cyclic tetrapeptide , 1974 .

[35]  Cecilia Clementi,et al.  Unfolding the fold of cyclic cysteine‐rich peptides , 2008, Protein science : a publication of the Protein Society.

[36]  Charles L. Brooks,et al.  Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures , 2004, J. Comput. Chem..

[37]  D. Case,et al.  Exploring protein native states and large‐scale conformational changes with a modified generalized born model , 2004, Proteins.

[38]  David J. Wales,et al.  Transition states and rearrangement mechanisms from hybrid eigenvector-following and density functional theory. Application to C10H10 and defect migration in crystalline silicon , 2001 .

[39]  G. Henkelman,et al.  A dimer method for finding saddle points on high dimensional potential surfaces using only first derivatives , 1999 .

[40]  D. Wales,et al.  A doubly nudged elastic band method for finding transition states. , 2004, The Journal of chemical physics.

[41]  Mark A. Miller,et al.  Archetypal energy landscapes , 1998, Nature.

[42]  David J. Wales,et al.  Free energy landscapes of model peptides and proteins , 2003 .

[43]  I. Carvalho,et al.  Diketopiperazines : biological activity and synthesis , 2007 .

[44]  F. Harris,et al.  The Dielectric Constant of Liquid Trifluoroacetic Acid1 , 1954 .

[45]  David J Wales,et al.  Thermodynamics and kinetics of aggregation for the GNNQQNY peptide. , 2007, Journal of the American Chemical Society.

[46]  Wei Zhang,et al.  A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations , 2003, J. Comput. Chem..

[47]  A. Klamt,et al.  COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient , 1993 .

[48]  D. Schmatz,et al.  Apicidins: Novel cyclic tetrapeptides as coccidiostats and antimalarial agents from Fusarium pallidoroseum , 1996 .

[49]  C. Tanford.  Macromolecules , 1994, Nature.

[50]  David J. Wales,et al.  Some further applications of discrete path sampling to cluster isomerization , 2004 .