Folding Very Short Peptides Using Molecular Dynamics

Ho, Bosco; Dill, Ken A.

doi:10.1371/journal.pcbi.0020027

Cited by 77 publications

(79 citation statements)

References 55 publications

(50 reference statements)

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“…STRUCTURE AND FUNCTION OF GOLDFISH SPEXIN defined 3D structure in aqueous solution, and their random structures can refold into structural elements under the hydrophobic environment close to the plasma membrane of target cells (7). Similar 3D conformation with random structures in the NH 2 terminus followed by an ␣-helix extended to the COOH terminus has also been reported in other neuropeptides, including pituitary adenylate cyclase-activating polypeptide (36), vasoactive intestinal peptide (39), and NPY (47).…”

Section: E362mentioning

confidence: 58%

Goldfish spexin: solution structure and novel function as a satiety factor in feeding control

Wong

Sze

Chen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

141

145

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Section: E362mentioning

confidence: 58%

Goldfish spexin: solution structure and novel function as a satiety factor in feeding control

Wong

Sze

Chen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

141

145

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“…We then determine whether each peptide finds a metastable structure, by the method described in ref. 49. We believe that this strategy may work in general, because 133 different peptides from six different proteins are found to be structured by using our same force-field approach (49).…”

Section: Methodsmentioning

confidence: 99%

Protein folding by zipping and assembly

Ozkan¹,

Wu²,

Chodera

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

139

146

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How do proteins fold so quickly? Some denatured proteins fold to their native structures in only microseconds, on average, implying that there is a folding "mechanism," i.e., a particular set of events by which the protein short-circuits a broader conformational search. Predicting protein structures using atomically detailed physical models is currently challenging. The most definitive proof of a putative folding mechanism would be whether it speeds up protein structure prediction in physical models. In the zipping and assembly (ZA) mechanism, local structuring happens first at independent sites along the chain, then those structures either grow (zip) or coalescence (assemble) with other structures. Here, we apply the ZA search mechanism to protein native structure prediction by using the AMBER96 force field with a generalized Born/surface area implicit solvent model and sampling by replica exchange molecular dynamics. Starting from open denatured conformations, our algorithm, called the ZA method, converges to an average of 2.2 Å from the Protein Data Bank native structures of eight of nine proteins that we tested, which ranged from 25 to 73 aa in length. In addition, experimental ⌽ values, where available on these proteins, are consistent with the predicted routes. We conclude that ZA is a viable model for how proteins physically fold. The present work also shows that physicsbased force fields are quite good and that physics-based protein structure prediction may be practical, at least for some small proteins.protein structure prediction ͉ replica-exchange molecular dynamics T here are two protein folding problems: one is physical and one computational. The physical problem is a puzzle about how proteins fold so quickly. In test-tube refolding experiments, protein molecules begin in a disordered denatured state (a broad ensemble of microscopic conformations) and then fold when native conditions are restored. On the one hand, folding must be stochastic: a protein's native structure is reached via many different microscopic trajectories from the broad ensemble of different starting denatured conformations. On the other hand, folding happens quickly, sometimes averaging only microseconds to reach the ordered native conformation (1). How does the process of searching and sorting through the protein's large conformational space of disordered states happen so rapidly? And how is the same native state reached from so many different starting conformations? This puzzle has been called ''Levinthal's Paradox'' (2). Even the simplest disorderto-order transitions, like the crystallization of sodium chloride, take days. It follows that the conformational search, although stochastic, cannot be random.The second folding problem is computational: predicting a protein's native structure from its amino acid sequence. Success in this area could lead to advances in computer-based drug discovery.

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“…Molecular modeling and molecular dynamics (MD) simulations are an emerging approach that explores the conformational landscape of short peptides enabling one to assess molecular structural differences that influence functional binding parameters. 16,17 In this study, we investigated fibrin knob peptide:hole interactions with both experimental and theoretical modeling approaches to elucidate factors that influence the kinetic binding dynamics (k a and k d ) of knob A peptide variants to fibrin holes. We focused on (1) kinetic modeling of the binding interaction and (2) structural characterization of the peptides in solution.…”

Section: Introductionmentioning

confidence: 99%

Building better fibrin knob mimics: an investigation of synthetic fibrin knob peptide structures in solution and their dynamic binding with fibrinogen/fibrin holes

Stabenfeldt

Gossett

Barker

2010

Blood

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Fibrin polymerizes via noncovalent and dynamic association of thrombin-exposed "knobs" with complementary "holes." Synthetic knob peptides have received significant interest as a means for understanding fibrin assembly mechanisms and inhibiting fibrin polymerization. Nevertheless, the inability to crystallize short peptides significantly limits our understanding of knob peptide structural features that regulate dynamic knob:hole interactions. In this study, we used molecular simulations to generate the first predicted structure(s) of synthetic knobs in solution before fibrin hole engagement. Combining surface plasmon resonance (SPR), we explored the role of structural and electrostatic properties of knob "A" mimics in regulating knob:hole binding kinetics. SPR results showed that association rates were most profoundly affected by the presence of both additional prolines as well as charged residues in the sixth to seventh positions. Importantly, analyzing the structural dynamics of the peptides through simulation indicated that the 3Arg side chain orientation and peptide backbone stability each contribute significantly to functional binding. These findings provide insights into early fibrin protofibril assembly dynamics as well as establishing essential design parameters for high-affinity knob mimics that more efficiently compete for hole occupancy, parameters realized here through a novel knob mimic displaying a 10-fold higher association rate than current mimics. IntroductionThe activation and polymerization of the blood-circulating protein fibrinogen, a 340-kDa glycoprotein with 6 polypeptide chains (A␣B␤␥) 2 , is the primary homeostatic mechanism preventing excessive blood loss after vascular injury. This process is initiated by the activated serine protease thrombin, which specifically cleaves 4 N-terminal arginyl-glycine motifs on the 2 adjacent A␣ and B␤ chains of fibrinogen, releasing 2 sets of fibrinopeptides A and B (FpA and FpB) and exposing cryptic fibrin polymerization knobs "A" and "B," respectively. 1-5 The newly exposed fibrin knobs noncovalently interact with complementary "holes"' within the 2 distal C-terminal regions of the ␥ and ␤ chains (complementary holes "a" and "b," respectively) to initiate fibrin protofibril assembly. Understanding the fundamentals of this dynamic and noncovalent knob:hole interaction will lead to both a more thorough understanding of fibrin assembly mechanisms and the establishment of design criteria for superior anticoagulants with high polymerization hole affinity to inhibit fibrin assembly.Evidence for fibrin knob:hole interactions was first conclusively shown when fibrin polymerization was inhibited by synthetic knob A tripeptides (Gly-Pro-Arg) competing for fibrin holes. 6,7 Characterization of the equilibrium binding affinities of both knob A and B peptide variants to fibrinogen showed that the knob A peptides (ie, GPRV and GPRP) have higher affinities to fibrinogen than knob B peptides (ie, GHRP and AHRP) under calcium-free conditions. [6][7][8] In the presenc...

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Folding Very Short Peptides Using Molecular Dynamics

Cited by 77 publications

References 55 publications

Goldfish spexin: solution structure and novel function as a satiety factor in feeding control

Goldfish spexin: solution structure and novel function as a satiety factor in feeding control

Protein folding by zipping and assembly

Building better fibrin knob mimics: an investigation of synthetic fibrin knob peptide structures in solution and their dynamic binding with fibrinogen/fibrin holes

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