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Reducing the computational complexity of protein folding via fragment folding and assembly.

ABSTRACT: Understanding, and ultimately predicting, how a 1-D protein chain reaches its native 3-D fold has been one of the most challenging problems during the last few decades. Data increasingly indicate that protein folding is a hierarchical process. Hence, the question arises as to whether we can use the hierarchical concept to reduce the practically intractable computational times. For such a scheme to work, the first step is to cut the protein sequence into fragments that form local minima on the polypeptide chain. The conformations of such fragments in solution are likely to be similar to those when the fragments are embedded in the native fold, although alternate conformations may be favored during the mutual stabilization in the combinatorial assembly process. Two elements are needed for such cutting: (1) a library of (clustered) fragments derived from known protein structures and (2) an assignment algorithm that selects optimal combinations to "cover" the protein sequence. The next two steps in hierarchical folding schemes, not addressed here, are the combinatorial assembly of the fragments and finally, optimization of the obtained conformations. Here, we address the first step in a hierarchical protein-folding scheme. The input is a target protein sequence and a library of fragments created by clustering building blocks that were generated by cutting all protein structures. The output is a set of cutout fragments. We briefly outline a graph theoretic algorithm that automatically assigns building blocks to the target sequence, and we describe a sample of the results we have obtained.

SUBMITTER: Haspel N

PROVIDER: S-EPMC2323902 | biostudies-literature | 2003 Jun

REPOSITORIES: biostudies-literature

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Reducing the computational complexity of protein folding via fragment folding and assembly.

Haspel Nurit N Tsai Chung-Jung CJ Wolfson Haim H Nussinov Ruth R

Protein science : a publication of the Protein Society 20030601 6

Understanding, and ultimately predicting, how a 1-D protein chain reaches its native 3-D fold has been one of the most challenging problems during the last few decades. Data increasingly indicate that protein folding is a hierarchical process. Hence, the question arises as to whether we can use the hierarchical concept to reduce the practically intractable computational times. For such a scheme to work, the first step is to cut the protein sequence into fragments that form local minima on the po ...[more]

PMID: 12761388

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Project description:A family of amphiphilic, heterograft copolymers containing hydrophilic, hydrophobic, and supramolecular units based on Jeffamine M-1000, dodecylamine, and benzene-1,3,5-tricarboxamide (BTA) motifs, respectively, was prepared via a postfunctionalization approach. The folding of the copolymers in water into nanometer-sized particles was analyzed by a combination of dynamic and static light scattering, circular dichroism spectroscopy, and small-angle neutron scattering. The sample preparation protocol was crucial for obtaining reproducible and consistent results, showing that only full control over the structure and pathway complexity will afford the desired folded structure, a phenomenon similar to protein folding. The results revealed that relatively small changes in the polymer's graft composition strongly affected the intra- versus intermolecular assembly processes. Depending on the amount of the hydrophobic grafts based on either dodecyl or BTA groups, pronounced behavioral differences were observed for copolymers that comprise similar degrees of hydrophobic content. A high number of BTA grafts (>10%) resulted in the formation of multichain aggregates comprising around six polymer chains. In contrast, for copolymers comprising up to 10% BTA grafts the folding results in nanoparticles that adopt open, sparse conformations and comprise one to two polymer chains. Interestingly, predominantly single-chain polymeric nanoparticles were formed when the copolymer comprised only Jeffamine or Jeffamine and dodecyl grafts. In addition, replacing part of the BTA grafts by hydrophobic dodecyl grafts while keeping the hydrophobic content constant promoted single-chain folding and resulted in the formation of a compact, globular nanoparticle with a more structured interior. Thus, the intra- and intermolecular self-assembly pathways can be directed by carefully tuning the polymer's hydrophilic-hydrophobic balance in combination with the number of supramolecular grafts.

Project description:Although molecular simulation methods have yielded valuable insights into mechanistic aspects of protein refolding in vitro, they have up to now not been used to model the folding of proteins as they are actually synthesized by the ribosome. To address this issue, we report here simulation studies of three model proteins: chymotrypsin inhibitor 2 (CI2), barnase, and Semliki forest virus protein (SFVP), and directly compare their folding during ribosome-mediated synthesis with their refolding from random, denatured conformations. To calibrate the methodology, simulations are first compared with in vitro data on the folding stabilities of N-terminal fragments of CI2 and barnase; the simulations reproduce the fact that both the stability and thermal folding cooperativity increase as fragments increase in length. Coupled simulations of synthesis and folding for the same two proteins are then described, showing that both fold essentially post-translationally, with mechanisms effectively identical to those for refolding. In both cases, confinement of the nascent polypeptide chain within the ribosome tunnel does not appear to promote significant formation of native structure during synthesis; there are however clear indications that the formation of structure within the nascent chain is sensitive to location within the ribosome tunnel, being subject to both gain and loss as the chain lengthens. Interestingly, simulations in which CI2 is artificially stabilized show a pronounced tendency to become trapped within the tunnel in partially folded conformations: non-cooperative folding, therefore, appears in the simulations to exert a detrimental effect on the rate at which fully folded conformations are formed. Finally, simulations of the two-domain protease module of SFVP, which experimentally folds cotranslationally, indicate that for multi-domain proteins, ribosome-mediated folding may follow different pathways from those taken during refolding. Taken together, these studies provide a first step toward developing more realistic methods for simulating protein folding as it occurs in vivo.

Dataset Information

Reducing the computational complexity of protein folding via fragment folding and assembly.

Publications

Reducing the computational complexity of protein folding via fragment folding and assembly.

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