All-Atom Ab Initio Folding of a Diverse Set of Proteins

Yang, Jingge; Chen, William W.; Skolnick, Jeffrey; Shakhnovich, Eugene I.

doi:10.1016/j.str.2006.11.010

Cited by 89 publications

(97 citation statements)

References 40 publications

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“…Our All-Atom Monte Carlo program has been used to successfully predict folded states and relative mutant stabilities of single proteins in previous publications (46,49). Here, we used the program to simulate interactions between two proteins by connecting them by a flexible linker.…”

Section: Discussionmentioning

confidence: 99%

“…All-atom (non-hydrogen) Monte-Carlo simulations were performed using a program described in previous publications, developed by the Shakhnovich group (46)(47)(48)(49). The program incorporates a knowledge-based potential, with terms for contact energy, hydrogen-bonding, torsional angle, and sidechain torsional terms, as well as a term describing relative orientations of aromatic residues.…”

Section: Monte-carlo Unfolding Simulationsmentioning

confidence: 99%

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An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

Serebryany

Woodard

Adkar

et al. 2017

Biophysical Journal

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Considerable mechanistic insight has been gained into amyloid aggregation; however, a large class of non-amyloid protein aggregates are considered "amorphous," and in most cases little is known about their mechanisms. Amorphous aggregation of γ-crystallins in the eye lens causes a widespread disease of aging, cataract. We combined simulations and experiments to study the mechanism of aggregation of two γD-crystallin mutants, W42R and W42Q -the former a congenital cataract mutation, and the latter a mimic of age-related oxidative damage. We found that formation of an internal disulfide was necessary and sufficient for aggregation under physiological conditions. Twochain all-atom simulations predicted that one nonnative disulfide in particular, between Cys32 and Cys41, was likely to stabilize an unfolding intermediate prone to intermolecular interactions. Mass spectrometry and mutagenesis experiments confirmed the presence of this bond in the aggregates and its necessity for oxidative aggregation under physiological conditions in vitro. Mining the simulation data linked formation of this disulfide to extrusion of the N-terminal β-hairpin and rearrangement of the native β-sheet topology.

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Section: Discussionmentioning

confidence: 99%

Section: Monte-carlo Unfolding Simulationsmentioning

confidence: 99%

An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

Serebryany

Woodard

Adkar

et al. 2017

Biophysical Journal

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“…Consequently, our strategy may share some benefits that authentic proteins gain by folding along a robust and efficient pathway. Although others have integrated 2°a nd 3°structure determination (11,12) with an iterative fixing (ItFix) of 2°structure (13)(14)(15), our approach differs by (i) not using any exogenous 2°structure prediction or homology; (ii) removing side-chain degrees of freedom from the model, which greatly reduces computation time; and (iii) allowing the whole chain to interact throughout the entire folding process. Furthermore, our moves involve changes only in a single pair of dihedral angles ( , ) that is obtained from the Protein Data Base (PDB) and that includes the influence of the identity and 2°structure of the neighboring residues.…”

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confidence: 99%

Mimicking the folding pathway to improve homology-free protein structure prediction

DeBartolo¹,

Colubri²,

Jha³

et al. 2009

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

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Since the demonstration that the sequence of a protein encodes its structure, the prediction of structure from sequence remains an outstanding problem that impacts numerous scientific disciplines, including many genome projects. By iteratively fixing secondary structure assignments of residues during Monte Carlo simulations of folding, our coarse-grained model without information concerning homology or explicit side chains can outperform current homologybased secondary structure prediction methods for many proteins. The computationally rapid algorithm using only single ( , ) dihedral angle moves also generates tertiary structures of accuracy comparable with existing all-atom methods for many small proteins, particularly those with low homology. Hence, given appropriate search strategies and scoring functions, reduced representations can be used for accurately predicting secondary structure and providing 3D structures, thereby increasing the size of proteins approachable by homology-free methods and the accuracy of template methods that depend on a high-quality input secondary structure.protein folding ͉ secondary structure prediction ͉ tertiary structure prediction ͉ iterative fixing ͉ statistical potential T he protein folding process is integral to multiple cellular processes, and errors can result in amyloidgenic diseases. The structure of a protein affords a window on its function, and the huge growth in the number of sequenced genomes provides codes for an enormous number of new proteins with unknown functions (1), a number far exceeding experimental capabilities and requiring fast throughput theoretical methods for deducing protein structure from sequence. To this end, great progress in predicting structure has emerged by using homology-based methods (2).However, the goal of predicting structure and pathways beginning only from the sequence remains an elusive goal. Furthermore, methods for secondary and tertiary (2°and 3°) structure prediction, although often quite accurate, can fail for lack of sufficient sequences that are homologous to the target sequence. Even if a multiple sequence alignment (MSA) exists, e.g., as generated by using PSI-BLAST (3), the alignment may diminish any structural propensity that is specific to the target sequence (in its 3°context) in favor of the consensus of the alignment. This disadvantage can adversely affect 3°structure prediction because the homologybased 2°structure prediction and MSA generally serve as crucial inputs.The reliance on homology also precludes identifying the underlying physiochemical principles that govern protein folding, including determining the minimal information and model of protein structure that are required for accurate structure prediction. This inadequacy arises from the failure of many 2°structure prediction methods (4, 5) to incorporate 3°context explicitly. Context dependence can overrule local biases (6-8), and its neglect has limited 2°s tructure accuracy to Ϸ80% for decades (9). Previous attempts to improve 2°structure predictions by inc...

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“…Most attempts in this direction have assumed sequences to encode partial information about many structural properties, such as likelihood of tertiary contacts or secondary structure propensities, that could eventually be combined to provide a general predictive algorithm (6)(7)(8)(9)(10). An alternative scheme would assume a single (or few) conformational property to be directly encoded in sequences, resulting in a small number of sequence-dependent parameters, whereas other conformational features would arise from sequence-independent constraints.…”

mentioning

confidence: 99%

A sequence-compatible amount of native burial information is sufficient for determining the structure of small globular proteins

Araújo

Onuchic²

2009

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

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Protein tertiary structures are known to be encoded in amino acid sequences, but the problem of structure prediction from sequence continues to be a challenge. With this question in mind, recent simulations have shown that atomic burials, as expressed by atom distances to the molecular geometrical center, are sufficiently informative for determining native conformations of small globular proteins. Here we use a simple computational experiment to estimate the amount of this required burial information and find it to be surprisingly small, actually comparable with the stringent limit imposed by sequence statistics. Atomic burials appear to satisfy, therefore, minimal requirements for a putative dominating property in the folding code because they provide an amount of information sufficiently large for structural determination but, at the same time, sufficiently small to be encodable in sequences. In a simple analogy with human communication, atomic burials could correspond to the actual "language" encoded in the amino acid "script" from which the complexity of native conformations is recovered during the folding process.protein folding | structure prediction | information theory | folding code D uring the last two decades, a physical picture of the folding process has emerged with the advent of energy landscape theory (1-5) but, despite many recent advances, a general solution to the problem of structure prediction from sequence has remained elusive. Most attempts in this direction have assumed sequences to encode partial information about many structural properties, such as likelihood of tertiary contacts or secondary structure propensities, that could eventually be combined to provide a general predictive algorithm (6-10). An alternative scheme would assume a single (or few) conformational property to be directly encoded in sequences, resulting in a small number of sequence-dependent parameters, whereas other conformational features would arise from sequence-independent constraints. The importance of such constraints has been recently emphasized by Banavar and collaborators (11).The amount of information provided by a putative single property dominating the code should satisfy two conditions: It should be sufficiently large for structural determination but sufficiently small for being encodable in sequences (12). The widely recognized importance of hydrophobic interactions on protein structure formation (13,14) suggests atomic burials to constitute a natural candidate for this putative dominant property. There has been some discussion, in the simplified context of lattice models, on the possibility that intrinsically unspecific hydrophobicity could satisfy the first condition (15), including a dependence on the choice of native conformation (16,17). Encouraging results from recent Monte Carlo simulations, on the other hand, indicate that the first condition is satisfied by atomic burials, as measured by distances from the molecular geometrical center, for small globular proteins represented by off-lattice, geome...

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All-Atom Ab Initio Folding of a Diverse Set of Proteins

Cited by 89 publications

References 40 publications

An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

An Internal Disulfide Locks a Misfolded Aggregation-Prone Intermediate in Cataract-Linked Mutants of Human Gamma-D Crystallin

Mimicking the folding pathway to improve homology-free protein structure prediction

A sequence-compatible amount of native burial information is sufficient for determining the structure of small globular proteins

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