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Database-derived potentials dependent on protein size for in silico folding and design.

ABSTRACT: Knowledge-based potentials are widely used in simulations of protein folding, structure prediction, and protein design. Their advantages include limited computational requirements and the ability to deal with low-resolution protein models compatible with long-scale simulations. Their drawbacks comprehend their dependence on specific features of the dataset from which they are derived, such as the size of the proteins it contains, and their physical meaning is still a subject of debate. We address these issues by probing the theoretical validity of these potentials as mean-force potentials that take the solvent implicitly into account and involve entropic contributions due to atomic degrees of freedom and solvation. The dependence on the size of the system is checked on distance-dependent amino acid pair potentials, derived from six protein structure sets containing proteins of increasing length N. For large inter-residue distances, they are found to display the theoretically predicted 1/N behavior weighted by a factor depending on the boundaries and the compressibility of the system. For short distances, different trends are observed according to the nature of the residue pairs and their ability to form, for example, electrostatic, cation-pi or pi-pi interactions, or hydrophobic packing. The results of this analysis are used to devise a novel protein size-dependent distance potential, which displays an improved performance in discriminating native sequence-structure matches among decoy models.

SUBMITTER: Dehouck Y

PROVIDER: S-EPMC1304340 | biostudies-literature | 2004 Jul

REPOSITORIES: biostudies-literature

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Database-derived potentials dependent on protein size for in silico folding and design.

Dehouck Yves Y Gilis Dimitri D Rooman Marianne M

Biophysical journal 20040701 1

Knowledge-based potentials are widely used in simulations of protein folding, structure prediction, and protein design. Their advantages include limited computational requirements and the ability to deal with low-resolution protein models compatible with long-scale simulations. Their drawbacks comprehend their dependence on specific features of the dataset from which they are derived, such as the size of the proteins it contains, and their physical meaning is still a subject of debate. We addres ...[more]

PMID: 15240455

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Project description:BACKGROUND:Evolutionary information contained in the amino acid sequences of proteins specifies the biological function and fold, but exactly what information contained in the protein sequence drives both of these processes? Considerable progress has been made to answer this fundamental question, but it remains challenging to explore the potential space of cooperative interactions between amino acids. Statistical analysis plays a significant role in studying such interactions and its use has expanded in recent years to studies ranging from coevolution-guided rational protein design to protein folding in silico. RESULTS:Here we describe a computational tool named Sibe for use in studies of protein sequence, folding, and design using evolutionary coupling between amino acids as a driving factor. In this study, Sibe is used to identify positionally conserved couplings between pairwise amino acids and aid rational protein design. In this process, pairwise couplings are filtered according to the relative entropy computed from the positional conservations and grouped into several 'blocks', which could contribute to driving protein folding and design. A human ?2-adrenergic receptor (?2AR) was used to demonstrate that those 'blocks' contribute the rational design for specifying functional residues. Sibe also provides folding modules based on both the positionally conserved couplings and well-established statistical potentials for simulating protein folding in silico and predicting tertiary structure. Our results show that statistically inferences of basic evolutionary principles, such as conservations and coupled-mutations, can be used to rapidly design a diverse set of proteins and study protein folding. CONCLUSIONS:The developed software Sibe provides a computational tool for systematical analysis from protein primary to its tertiary structure using the evolutionary couplings as a driving factor. Sibe, written in C++, accounts for compatibility with the 'big data' era in biological science, and it primarily focuses on protein sequence analysis, but it is also applicable to extend to other modeling and predictions of experimental measurements.

Project description:Background: Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. Despite the remarkable progress that has been achieved by the artificial intelligence approaches in predicting the protein native conformations, the pathways that lead to such conformations, either in vitro or in vivo, remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such a protein folding machine might include direct manipulation of the peptide backbone. Methods: To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Results: Remarkably, the addition of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Steric clashes that arise in the peptides due to the forced directional rotation resulted in the behavior of the peptide backbone no longer resembling a freely jointed chain. Conclusions: These simulations show the feasibility of a protein folding machine operating under the conditions when the movements of the polypeptide backbone are restricted by applying external forces and constraints. Further investigation is needed to see whether such an effect may play a role during co-translational protein folding in vivo and how it can be utilized to facilitate folding of proteins in artificial environments.

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Database-derived potentials dependent on protein size for in silico folding and design.

Publications

Database-derived potentials dependent on protein size for in silico folding and design.

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