Conformational analysis of thiopeptides: derivation of sp2 sulfur parameters for the CFF91 force field

Tran, Tran Trung; Treutlein, Herbert; Burgess, Antony W.

doi:10.1002/jcc.1062.abs

Cited by 5 publications

(13 citation statements)

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“…The crystal structures for both Ac‐Alat‐NHMe and Act‐Ala‐NHMe provided an excellent opportunity for validating our recently derived CFF91 force field thioamide parameters (26,27) by comparing the calculated and the observed (φ, ψ) dihedral angles.…”

Section: Resultsmentioning

confidence: 97%

“… (φ, ψ) conformational energy maps for (A) Act‐Ala‐NHMe and (B) Ac‐Ala‐NHMe obtained by energy minimization with torsion forcing at every 10° increment of φ and ψ dihedral angles. Calculations were performed using the parameters from the CFF91 force field and the sp 2 sulfur parameters derived as described in the previous study in this series (26). The maps are colored white in low‐energy regions and black in high‐energy regions.…”

Section: Resultsmentioning

confidence: 99%

“…In the previous studies in this series (26,27), we derived sp 2 sulfur parameters for the CFF91 force field (28–30) and predicted that the thio substitution would restrict the conformational space available to the dipeptides as well as alter both the intramolecular and intermolecular hydrogen bonds. While the seven thio‐containing crystal structures for dithiomalonodiamide (31), thioacetamide (32), Boc‐Alat‐NHCH 3 (13) (Z)‐Glyt‐Gly‐OBzl (33), Boc‐Gly‐Alat‐Aib‐OMe (34), Boc‐Glyt‐Ala‐Aib‐OMe (34) and (Z)‐Glyt‐Glyt‐Gly‐OBzl (35) were used to evaluate the parameters and the accuracy of the calculated empirical conformational energy, they were nonideal candidates because all the molecules were end‐protected by bulky groups or contained the Aib residue, and therefore may have biased the conformation of an individual residue away from its global minimum in a dipeptide or peptide environment.…”

Section: Abbreviationsmentioning

confidence: 99%

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Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp² sulfur parameters of the CFF91 force field

Tran

Burgess

Treutlein

et al. 2001

The Journal of Peptide Research

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Acetyl thioalanine N-methyl (Ac-Alat-NHMe) and thioacetyl alanine N-methyl (Act-Ala-NHMe) were synthesized, crystallized and their X-ray diffraction structures determined for the first time. Both molecules adopted beta-sheet conformations and showed similar hydrogen bonding patterns with one molecular surface forming two oxo hydrogen bonds and the other forming two thio hydrogen bonds. The crystal structure data for the two thioamides provided a validation of the thioamide parameters for the newly derived CFF91 force field because the observed crystal (phi, psi) angles were situated in the global minimum regions of the theoretical (phi, psi) map predicted using the parameters. In addition, the parameters were further validated because conformational energy minimization of the crystal structure produced low deviations in unit cell dimensions, bond lengths, bond angles and torsional angles, and a 120-ps molecular dynamics simulation also gave a low deviation for the most probable N-H...S=C bond distance.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Abbreviationsmentioning

confidence: 99%

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Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp² sulfur parameters of the CFF91 force field

Tran

Burgess

Treutlein

et al. 2001

The Journal of Peptide Research

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“…In this modification, the backbone hydrogen‐bond acceptor oxygen is replaced by sulfur thereby reducing the hydrogen‐bond forming capability of the backbone. Many computational and experimental studies on different thiopeptides have been reported in the past decade 14–19. To further investigate the effect of varying the strength and geometry of hydrogen bonds involving the backbone in protein folding, it will be of interest to see whether partly or fully thionated HEWL is still able to maintain the structural properties of native HEWL.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation of thionated hen egg white lysozyme

2012

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Understanding of the driving forces of protein folding is a complex challenge because different types of interactions play a varying role. To investigate the role of hydrogen bonding involving the backbone, the effect of thio substitutions in a protein, hen egg white lysozyme (HEWL), was investigated through molecular dynamics simulations of native as well as partly (only residues in loops) and fully thionated HEWL using the GROMOS 54A7 force field. The results of the three simulations show that the structural properties of fully thionated HEWL clearly differ from those of the native protein, while for partly thionated HEWL they only changed slightly compared with native HEWL. The analysis of the torsional-angle distributions and hydrogen bonds in the backbone suggests that the a-helical segments of native HEWL tend to show a propensity to convert to 3 10 -helical geometry in fully thionated HEWL. A comparison of the simulated quantities with experimental NMR data such as nuclear overhauser effect (NOE) atom-atom distance bounds and 3 J H N H acouplings measured for native HEWL illustrates that the information content of these quantities with respect to the structural changes induced by thionation of the protein backbone is rather limited.

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“…A great deal of scientific effort has been applied to classify, design and synthesize b-turn mimetics [47,[55][56][57][58][59][60][61][62][63][64][65][66][67][68]. To compare our clustering of loops with the traditional b-turn type classification as defined by Hutchinson and Thornton [69], the loops in the vector plots in Fig.…”

Section: Relationship Between the 39 Clustersmentioning

confidence: 99%

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Tran

Kulis

Long

et al. 2010

J Comput Aided Mol Des

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Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.

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Conformational analysis of thiopeptides: derivation of sp2 sulfur parameters for the CFF91 force field

Cited by 5 publications

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Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp² sulfur parameters of the CFF91 force field

Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp² sulfur parameters of the CFF91 force field

Molecular dynamics simulation of thionated hen egg white lysozyme

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

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Conformational analysis of thiopeptides: derivation of sp2 sulfur parameters for the CFF91 force field

Cited by 5 publications

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Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp2 sulfur parameters of the CFF91 force field

Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp2 sulfur parameters of the CFF91 force field

Molecular dynamics simulation of thionated hen egg white lysozyme

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

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Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp² sulfur parameters of the CFF91 force field

Synthesis, X‐ray crystallographic structures of thio substituted N‐acetyl N′‐methylamide alanine and evaluation of sp² sulfur parameters of the CFF91 force field