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Results for “Molecular Docking Simulation”

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PubMed2004

Molecular recognition in purinergic receptors. 1. A comprehensive computational study of the h-P2Y1-receptor.

P2Y receptors (P2Y-Rs) are attractive pharmaceutical targets due to their involvement in the modulation of many tissues and organs. The lack of experimental structural data on P2Y-Rs impedes structure-based drug design. The need to elucidate the receptor's molecular recognition, together with the limitations of previous receptor models, triggered the construction of a new molecular model for the h-P2Y1-R. Therefore, a h-P2Y1-R model was constructed by homology modeling using the 2.6 A crystal structure of bovine rhodopsin as a template and subsequently refined by constrained molecular dynamics (MD) simulations in a fully hydrated lipid bilayer environment. ATP was docked into the receptor binding site, followed by binding site refinement using Monte Carlo and MD simulations. Analysis of the h-P2Y1-R-ATP complex suggests that the triphosphate moiety is tightly bound by a multitude of interactions possibly including a Mg2+ ion, the ribose ring is not involved in specific interactions, and the adenine ring is bound via N1, N7, and N6. The molecular recognition of the h-P2Y1-R was further probed by ATP derivatives modified on the adenine ring, and correlated with EC50 values for these derivatives. Analysis of receptor:ligand complexes and quantum mechanical studies on model compounds support the role of both steric and electronic effects in improving H-bonding (via N1 and N6) and pi-stacking interactions. The computed h-P2Y1-R model was validated with respect to our previous biochemical results. We believe that this new model of the h-P2Y1-R provides the means for understanding phenomena such as the ligand's potency and receptor subtype selectivity.

Adenosine Triphosphate↗

PubMed1998

Molecular anchors with large stability gaps ensure linear binding free energy relationships for hydrophobic substituents.

Ligand-protein docking simulations are employed to analyze the binding energy landscape of the pipecolinyl fragment that serves as a recognition core of the FK506 ligand in binding with the FKBP12 protein. This fragment acts as a molecular anchor that specifically binds within the protein active site in a unique binding mode, in harmony with the structure of the FK506-FKBP12 complex. Molecular anchors are characterized by a large stability gap, defined to be the free energy of a ligand bound in the native binding mode relative to the free energy of alternative binding modes. For ligands that share a common anchor fragment, a linear binding free energy relationship may be expected for hydrophobic substituents provided they do not abrogate the anchor binding mode. Changes in solvent-accessible surface area for these peripheral groups are used to rationalize the relative binding affinities of a series of FKBP12-ligand complexes which share the pipecolinyl anchor fragment. A series of benzene derivatives that bind to a mutant form of T4 lysozyme is also analyzed, and implications for structure-based drug design are discussed.

Allosteric Site↗

PubMed2002

CoMFA and CoMSIA 3D QSAR and docking studies on conformationally-restrained cinnamoyl HIV-1 integrase inhibitors: exploration of a binding mode at the active site.

Anti-HIV (human immunodeficiency virus) drug discovery has been increasingly focusing on HIV integrase (IN) as a potential therapeutic target. This enzyme is required for the integration of reverse transcribed proviral DNA into the host cell's genome and is essential for the propagation of the HIV life cycle. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D QSAR) studies and docking simulations were conducted on a series of potent conformationally restrained cinnamoyl inhibitors of HIV-1 IN (Artico; et al. J. Med. Chem. 1998, 41, 3948-3960). Predictive 3D QSAR models were established using SYBYL multifit molecular alignment rule, which had conventional r(2) and cross-validated coeffiecient (q(2)) values up to 0.981 and 0.721 for CoMFA and 0.975 and 0.804 for CoMSIA, respectively. These models were validated by an external test set (Burke; et al. J. Med. Chem. 1995, 38, 4171-4178). CoMFA and CoMSIA 3D QSAR models were also derived using a molecular alignment obtained by docking the compounds into the active site of HIV IN. These latter models were comparable to multifit-derived models in terms of relative descriptor field contributions and the partial least squares (PLS) contour maps. The CoMSIA 3D QSAR models performed better than the CoMFA models. The superior performance of CoMSIA was attributed to the large contribution of hydrogen-bonding interactions to the inhibitory activity differences among the compounds. This was supported by FlexX binding energy scores that correlated well with the inhibitory activity differences between hydroxylated compounds and their corresponding methoxy or deoxy counterparts. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking results, were integrated to propose a binding mode for the cinnamoyl inhibitors at the active site of HIV-1 IN.

Binding Sites↗

PubMed2003

Understanding the selectivity of fumagillin for the methionine aminopeptidase type II.

The aim of this study is to explain the selectivity of the antiangiogenic drug fumagillin for the eukaryotic enzyme methionine aminopeptidase type II (MetAP-II, EC 3.4.11.18) over the structurally very similar MetAP-I. A homology model for the human MetAP-I is constructed and molecular dynamics simulations are performed on this model with and without a docked fumagillin molecule. These simulations are compared with analogous simulations that were performed on the experimentally determined structure of the human MetAP-II enzyme. We observe an increased flexibility of the active site histidine that is covalently modified by fumagillin in the MetAP-I enzyme. The MetAP-I active site residues, particularly the fumagillin-binding histidine, have a lower probability to be in a conformation that is prone to react with the drug than their MetAP-II counterparts. This result offers an explanation for the selectivity of fumagillin for the eukaryotic MetAP-II enzyme.

Amino Acid Sequence↗

PubMed2006

A novel computational analysis of ligand-induced conformational changes in the ATP binding sites of cyclin dependent kinases.

Protein kinases in general are known to be very flexible macromolecules. In this article, the conformational plasticity of the ATP binding site in cyclin dependent kinases is analyzed. Movement of the two lysine residues lining the ATP binding site are shown to play a major role in the conformational variability of the site. Linear models are developed to identify and quantify ligand properties that maximally influence the lysine side chain conformations. A few simple properties of the ligands are shown to account for more than 70% of the variation in the lysine conformations. The results are validated using test data and molecular simulation studies. Illustrative applications of the results of this analysis to finding the appropriate crystal structure for molecular docking and binding mode predictions of novel ligands are provided. This work provides a new approach to quantify ligand-induced conformational changes in the active sites of flexible proteins and to find the appropriate crystal structure for docking novel ligands.

Adenosine Triphosphate↗

PubMed1994

A proposed model of bradykinin bound to the rat B2 receptor and its utility for drug design.

A putative model of bradykinin bound to the rat B2 receptor was generated using a combination of homology modeling (from the known transmembrane structure of bacteriorhodopsin), energy minimization, molecular dynamics, and a two-stage conformational search as a docking simulation. Overall, the proposed bound ligand adopts a twisted "S" shape, wherein a C-terminal beta-turn is buried in the receptor just below the extracellular boundary of the cell membrane and the N-terminus is interacting with negatively charged residues in extracellular loop 3 of the receptor (most notably Asp268 and Asp286). Mutagenesis experiments describing mutations which result in both a loss of bradykinin affinity as well as those which have no effect on bradykinin affinity are in good agreement with the proposed structure. In short, the mutagenesis results and the computational simulations each point to the same region of the receptor as likely to bind bradykinin. A double mutation, predicted as being likely to have a dramatic effect on bradykinin binding affinity, was confirmed experimentally, adding some validation to the proposed complex. Moreover, a new pseudopeptide bradykinin receptor antagonist (D-Arg0-Arg1-[12-aminododecanoyl]2- Ser3-D-Tic4-Oic5-Arg6) was designed on the basis of the model, and found to have good receptor affinity. Speculation regarding other possible sites for mutagenesis are also described.

Alanine↗

PubMed2002

The cytoplasmic tail of invariant chain regulates endosome fusion and morphology.

The major histocompatibility complex class II associated invariant chain (Ii) has been shown to inhibit endocytic transport and to increase the size of endosomes. We have recently found that this property has a significant impact on antigen processing and presentation. Here, we show in a cell-free endosome fusion assay that expression of Ii can increase fusion after phosphatidylinositol 3-kinase activity is blocked by wortmannin. In live cells wortmannin was also not able to block formation of the Ii-induced enlarged endosomes. The effects of Ii on endosomal transport and morphology depend on elements within the cytoplasmic tail. Data from mutagenesis analysis and nuclear magnetic resonance-based structure calculations of the Ii cytoplasmic tail demonstrate that free negative charges that are not involved in internal salt bridges are essential for both interactions between the tails and for the formation of enlarged endosomes. This correlation indicates that it is interactions between the Ii cytoplasmic tails that are involved in endosome fusion. The combined data from live cells, cell-free assays, and molecular dynamic simulations suggest that Ii molecules on different vesicles can promote endosome docking and fusion and thereby control endosomal traffic of membrane proteins and endosomal content.

Amino Acid Sequence↗

PubMedDate not supplied

Mapping the binding site of a large set of quinazoline type EGF-R inhibitors using molecular field analyses and molecular docking studies.

In the current work, three-dimensional QSAR studies for one large set of quinazoline type epidermal growth factor receptor (EGF-R) inhibitors were conducted using two types of molecular field analysis techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). These compounds belonging to six different structural classes were randomly divided into a training set of 122 compounds and a test set of 13 compounds. The statistical results showed that the 3D-QSAR models derived from CoMFA were superior to those generated from CoMSIA. The most optimal CoMFA model after region focusing bears significant cross-validated r(2)(cv) of 0.60 and conventional r(2) of 0.92. The predictive power of the best CoMFA model was further validated by the accurate estimation to these compounds in the external test set, and the mean agreement of experimental and predicted log(IC(50)) values of the inhibitors is 0.6 log unit. Separate CoMFA models were conducted to evaluate the influence of different partial charges (Gasteiger-Marsili, Gasteiger-Hückel, MMFF94, ESP-AM1, and MPA-AM1) on the statistical quality of the models. The resulting CoMFA field map provides information on the geometry of the binding site cavity and the relative weights of various properties in different site pockets for each of the substrates considered. Moreover, in the current work, we applied MD simulations combined with MM/PBSA (Molecular mechanics/Possion-Boltzmann Surface Area) to determine the correct binding mode of the best inhibitor for which no ligand-protein crystal structure was present. To proceed, we define the following procedure: three hundred picosecond molecular dynamics simulations were first performed for the four binding modes suggested by DOCK 4.0 and manual docking, and then MM/PBSA was carried out for the collected snapshots. The most favorable binding mode identified by MM/PBSA has a binding free energy about 10 kcal/mol more favorable than the second best one. The most favorable binding mode identified by MM/PBSA can give satisfactory explanation of the SAR data of the studied molecules and is in good agreement with the contour maps of CoMFA. The most favorable binding mode suggests that with the quinazoline-based inhibitor, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 766, not Thr 830 as proposed by Wissner et al. (J. Med. Chem. 2000, 43, 3244). The predicted complex structure of quinazoline type inhibitor with EGF-R as well as the pharmacophore mapping from CoMFA can interpret the structure activities of the inhibitors well and afford us important information for structure-based drug design.

Binding Sites↗

PubMed2006

Structural features of the reprolysin atrolysin C and tissue inhibitors of metalloproteinases (TIMPs) interaction.

Atrolysin C is a P-I snake venom metalloproteinase (SVMP) from Crotalus atrox venom, which efficiently degrades capillary basement membranes, extracellular matrix, and cell surface proteins to produce hemorrhage. The tissue inhibitors of metalloproteinases (TIMPs) are effective inhibitors of matrix metalloproteinases which share some structural similarity with the SVMPs. In this work, we evaluated the inhibitory profile of TIMP-1, TIMP-2, and the N-terminal domain of TIMP-3 (N-TIMP-3) on the proteolytic activity of atrolysin C and analyzed the structural requirements and molecular basis of inhibitor-enzyme interaction using molecular modeling. While TIMP-1 and TIMP-2 had no inhibitory activity upon atrolysin C, the N-terminal domain of TIMP-3 (N-TIMP-3) was a potent inhibitor with a K(i) value of approximately 150nM. The predicted docking structures of atrolysin C and TIMPs were submitted to molecular dynamics simulations and the complex atrolysin C/N-TIMP-3 was the only one that maintained the inhibitory conformation. This study is the first to shed light on the structural determinants required for the interaction between a SVMP and a TIMP, and suggests a structural basis for TIMP-3 inhibitory action and related proteins such as the ADAMs.

Amino Acid Sequence↗

PubMed2005

Architecture of the human urotensin II receptor: comparison of the binding domains of peptide and non-peptide urotensin II agonists.

The human urotensin II receptor (h-UTR) is a member of the family of rhodopsin-like G-protein-coupled receptors (GPCRs) involved in the modulation of the functionality of many tissues and organs. Recently the urotensin-II (UII) neuropeptide, which is a potent vasoconstrictor in mammals and it is postulated to play a central role in cardiovascular homeostasis, has been identified as an agonist of the UII receptor. To elucidate the receptor's molecular recognition, a h-UTR model was constructed by homology modeling using the 2.6 A crystal structure of bovine rhodopsin as a template and subsequently refined by molecular dynamics simulations. The molecular recognition of h-UTR was probed by automated docking of P5U, a potent UII peptide agonist, as well as of the non-peptide compounds 1-4. We believe that this new model of the h-UTR provides the means for understanding the ligand's potency and for facilitating the design of novel and more potent UII ligands.

Amino Acid Sequence↗

PubMed2001

Insights into the structure and function of 5-HT(2) family serotonin receptors reveal novel strategies for therapeutic target development.

5-HT(2) family serotonin receptors, principal sites of action of serotonin in the brain, represent major molecular targets for drugs used in treating a variety of diseases including schizophrenia, depression, anxiety, eating disorders, obsessive-compulsive disorder, chronic pain conditions and obesity. The 5-HT(2) family of receptors has three members: 5-HT(2A), 5-HT(2B) and 5-HT(2C). Therefore, it is likely that subtype-selective compounds will be needed to avoid serious side effects and to enhance therapeutic indices. Unfortunately, recent insights into the structure and function of 5-HT(2A) receptors have revealed that structurally-diverse agonists and antagonists have distinct modes of interacting with 5-HT(2A) receptors, complicating efforts at structure-based drug-design. These distinct binding modes would not have been predicted based on conventional structure-activity relationships or static docking models. Fortunately, these complicated binding modes can be predicted and simulated using molecular dynamics, allowing for the possibility of structure-based drug design. Thus, provided appropriately sophisticated drug design strategies are employed, it is likely that uniquely valuable medications will result which could have great potential for treating a variety of mental and physical illnesses.

Journal Article↗

PubMed2003

Modeling domino effects in enzymes: molecular basis of the substrate specificity of the bacterial metallo-beta-lactamases IMP-1 and IMP-6.

Metallo-beta-lactamases can hydrolyze a broad spectrum of beta-lactam antibiotics and thus confer resistance to bacteria. For the Pseudomonas aeruginosa enzyme IMP-1, several variants have been reported. IMP-6 and IMP-1 differ by a single residue (glycine and serine at position 196, respectively), but have significantly different substrate spectra; while the catalytic efficiency toward the two cephalosporins cephalothin and cefotaxime is similar for both variants, IMP-1 is up to 10-fold more efficient than IMP-6 toward cephaloridine and ceftazidime. Interestingly, this biochemical effect is caused by a residue remote from the active site. The substrate-specific impact of residue 196 was studied by molecular dynamics simulations using a cationic dummy atom approach for the zinc ions. Substrates were docked in an intermediate structure near the transition state to the binding site of IMP-1 and IMP-6. At a simulation temperature of 100 K, most complexes were stable during 1 ns of simulation time. However, at higher temperatures, some complexes became unstable and the substrate changed to a nonactive conformation. To model stability, six molecular dynamics simulations at 100 K were carried out for all enzyme-substrate complexes. Stable structures were further heated to 200 and 300 K. By counting stable structures, we derived a stability ranking score which correlated with experimentally determined catalytic efficiency. The use of a stability score as an indicator of catalytic efficiency of metalloenzymes is novel, and the study of substrates in a near-transition state intermediate structure is superior to the modeling of Michaelis complexes. The remote effect of residue 196 can be described by a domino effect: upon replacement of serine with glycine, a hole is created and a stabilizing interaction between Ser196 and Lys33 disappears, rendering the neighboring residues more flexible; this increased flexibility is then transferred to the active site.

Amino Acid Substitution↗

PubMedDate not supplied

Towards understanding the mechanisms of molecular recognition by computer simulations of ligand-protein interactions.

The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand-protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand-protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well-optimized ligand-protein systems such as MTX-DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure.

Animals↗

PubMed1997

Assessment of the interaction between urokinase and reactive site mutants of protein C inhibitor.

Urokinase-type plasminogen activator (uPA) is a serine protease involved in pericellular proteolysis and tumor cell metastasis via plasmin-mediated degradation of extracellular matrix proteins. Plasma uPA is inhibited by the serine protease inhibitor protein C inhibitor (PCI) by the insertion of PCI's reactive site loop into the active site of the protease. To better understand the structural aspects of this inhibition, 15 reactive-site mutants of recombinant PCI (rPCI) were assayed for differences in uPA inhibition. These assays revealed that substitutions at the P1 Arg354 and P3 Thr352 sites of rPCI were detrimental to inhibitory activity, while P3' Arg357 mutations had little effect upon the inhibition rate. However, replacement of the P2 Phe353 with small residues like Ala and Gly increased the effectiveness of rPCI three- to four fold. To explain these altered rates of inhibition, a computer-derived molecular model of uPA was generated and docked to a model of PCI to simulate complex formation. The changes made by mutagenesis were then recreated in the model of uPA-PCI. In accordance with the kinetic data, the poor performance of P3 variants is primarily attributable to charge repulsion, while alleviation of steric hindrance at P2 produces the observed increase in uPA inhibition. In the model, residues at P3' interact with PCI rather than uPA, consistent with P3' variants demonstrating that little variation from wild-type activity. Ultimately, this combination of mutagenesis and molecular modeling will further refine our understanding of the interaction between PCI and uPA.

Amino Acid Sequence↗

PubMed2004

Synthesis, screening, and molecular modeling of new potent and selective antagonists at the alpha 1d adrenergic receptor.

In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the alpha(1d) adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three alpha(1)-AR subtypes and of the 5-HT(1A) receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the alpha(1d)-AR and the 5-HT(1A) receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BMY 7378 and 69 into the putative binding sites of the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR, and the 5-HT(1A) receptors suggest that the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4, 5, 6 and extracellular loop 2 (E2), whereas the spirocyclic ring of the ligand docks into a site formed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SAR data produced in this work. Furthermore, the binding site of the imide moiety does not allow for the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding interactions, consistent with the SAR data, in particular with the results obtained with the lactam derivative 128. The results of docking simulations also suggest that the second and third extracellular loops may act as selectivity filters for the substituted phenylpiperazines. The most potent and selective compounds for alpha(1d) adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073), are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2005

Conformational analysis of heparin binding peptides.

A properly engineered biomaterial for dental/orthopaedic applications must induce specific responses from the osteoblasts at the implant site. A most desirable response is an efficient adhesion, as it represents the first phase in the cell/material interaction and the quality of this phase will influence the cell's capacity to organize into a new functional tissue. The four osteoblast-adhesive peptides discussed in this paper are mapped on the 339-364 sequence (339MAPRPSLAKKQRFRHRNRKGYRSQRG364) located in the primary heparin-binding site of human vitronectin (HVP). Adsorbed on a polystyrene scaffold, these peptides display different adhesive activities towards osteoblasts. In this paper we report on the structural analysis in solution of the peptides through NMR and computational techniques. We find that the peptides with the highest adhesive activities display a hydrophobic patch opposite to the charged surface candidate to interact with heparin. These findings suggest that the peptides might adsorb on the polystyrene support in a favourable orientation for their activity. Furthermore, molecular models obtained for the four peptides in solution were used in rigid docking simulations with a heparin model. Assuming that the peptide solution conformations are not very different from the polystyrene-adsorbed structures, the simulations reveal that peptide adhesive activity is also affected by the number of ionic interactions and spacing between charged residues.

Amino Acid Sequence↗

PubMed2001

Molecular modeling of interactions of the non-peptide antagonist YM087 with the human vasopressin V1a, V2 receptors and with oxytocin receptors.

The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH2, AVP) and oxytocin (CYIQNCPLG-NH2, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH control (via stimulation of V1b receptors, V1bR, in the pituitary) and labor and lactation control (via stimulation of OT receptors, OTR, in the uterus and nipples, respectively). All four receptor subtypes belong to the GTP-binding (G) protein-coupled receptor (GPCR) family. This work consists of docking of YM087, a potent non-peptide V1aR and V2R - but not OTR - antagonist, into the receptor models based on relatively new theoretical templates of rhodopsin (RD) and opiate receptors, proposed by Mosberg et al. (Univ. of Michigan, Ann Arbor, USA). It is simultaneously demonstrated that this RD template satisfactorily compares with the first historical GPCR structure of bovine rhodopsin (Palczewski et al., 2000) and that homology-modeling of V2R, V1aR and OTR using opiate receptors as templates is rational, based on relatively high (20-60%) sequence homology among the set of 4 neurophyseal and 4 opiate receptors. YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA). From about 80 diverse configurations, sampled for each of the three ligand/receptor systems, 3 best energy-relaxed complexes were selected for mutual comparisons. Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data.

Amino Acid Sequence↗

PubMed2003

The complete folding pathway of a protein from nanoseconds to microseconds.

Combining experimental and simulation data to describe all of the structures and the pathways involved in folding a protein is problematical. Transition states can be mapped experimentally by phi values, but the denatured state is very difficult to analyse under conditions that favour folding. Also computer simulation at atomic resolution is currently limited to about a microsecond or less. Ultrafast-folding proteins fold and unfold on timescales accessible by both approaches, so here we study the folding pathway of the three-helix bundle protein Engrailed homeodomain. Experimentally, the protein collapses in a microsecond to give an intermediate with much native alpha-helical secondary structure, which is the major component of the denatured state under conditions that favour folding. A mutant protein shows this state to be compact and contain dynamic, native-like helices with unstructured side chains. In the transition state between this and the native state, the structure of the helices is nearly fully formed and their docking is in progress, approximating to a classical diffusion-collision model. Molecular dynamics simulations give rate constants and structural details highly consistent with experiment, thereby completing the description of folding at atomic resolution.

Animals↗