Showing papers on "Contact order published in 2018"

Effect of a salt-bridge between inter-repeats on the 3D structure of the c-Myb DNA-binding domain revealed by thermodynamic analysis

Abstract: Structure folding dictates protein functions. Recent advances in structural analysis such as NMR and X-ray crystallography enabled to determine protein structures at high resolution, which helps understanding of protein folding and recognition mechanisms. Additionally, solution thermodynamic analysis provides useful information to visualize the real behavior of proteins because they largely fluctuate in solution. In this study, we analyzed the effect of a putative salt-bridge between His-137 and Asp-178 in the c-Myb DNA-binding domain on the thermodynamics of its folding and motion. The minimum unit for specific DNA-binding of c-Myb consists of the two repeats, R2 and R3. The residues, His-137 and Asp-178, are located in R2 and R3, respectively, and are spatial proximity, possibly forming a salt-bridge as revealed by a previous crystal structure analysis. D178N mutation caused slight changes in the tertiary structure of R2R3. The thermal stability of the D178N mutant in the absence of DNA was much lower than that of wild-type R2R3. The decrease in stability was due to unfavorable enthalpy change, partially compensated by the favorable entropy change. The largely decreased enthalpy change indicated that the disruption of the salt-bridge weakens the overall intramolecular interactions in the folded state. Additionally, the increased entropy change indicated that the dynamics of the folded state increase upon mutation. In contrast, the D178N mutation slightly affected the thermal stability of the DNA-bound state, indicating that the salt-bridge is required for proper folding of R2R3 in the DNA-free state.

Folding with a protein's native shortcut network

Abstract: A complex network approach to protein folding is proposed, wherein a protein's contact map is reconceptualized as a network of shortcut edges, and folding is steered by a structural characteristic of this network. Shortcut networks are generated by a known message passing algorithm operating on protein residue networks. It is found that the shortcut networks of native structures (SCN0s) are relevant graph objects with which to study protein folding at a formal level. The logarithm form of their contact order (SCN0_lnCO) correlates significantly with folding rate of two-state and nontwo-state proteins. The clustering coefficient of SCN0s (CSCN0 ) correlates significantly with folding rate, transition-state placement and stability of two-state folders. Reasonable folding pathways for several model proteins are produced when CSCN0 is used to combine protein segments incrementally to form the native structure. The folding bias captured by CSCN0 is detectable in non-native structures, as evidenced by Molecular Dynamics simulation generated configurations for the fast folding Villin-headpiece peptide. These results support the use of shortcut networks to investigate the role protein geometry plays in the folding of both small and large globular proteins, and have implications for the design of multibody interaction schemes in folding models. One facet of this geometry is the set of native shortcut triangles, whose attributes are found to be well-suited to identify dehydrated intraprotein areas in tight turns, or at the interface of different secondary structure elements.

Shielding effect in protein folding.

Abstract: One of the most important interactions responsible for protein folding and stability are hydrogen bonds between peptide groups. There is a constant competition between the water molecules and peptide groups in a hydrogen bond formation. Also side-chains take part in this process by reducing hydration of peptide group (shielding effect) that promotes the protein folding. In this paper, a new approach to take into account a shielding effect is presented. A modification of the energy function is derived and incorporated into the UNited RESidue (UNRES) force field. Canonical Molecular Dynamics and Replica Exchange Molecular Dynamics with UNRES force field is applied to study the influence of this effect on protein structure, folding kinetics and free energy landscapes. The results of test calculations suggest that even small contribution of this effect into energy function changes force field behavior as well as speeds up the folding process significantly.

A topological order parameter for describing folding free energy landscapes of proteins.

Abstract: We studied the refolding free energy landscape of 26 proteins using the Go-like model. The distance between the denaturated state and the transition state, XF, was calculated using the Bell theory and the nonlinear Dudko-Hummer-Szabo theory, and its relation to the geometrical properties of the native state was considered in detail. We showed that none of the structural parameters, such as the contact order, protein length, and radius of cross section, correlate with XF for all classes of proteins. To overcome this problem, we have introduced the nematic order parameter P02, which describes the ordering of the structured elements of the native state. Due to its topologically global nature, P02 is better than other structural parameters in describing the folding free energy landscape. In particular, P02 displays a good correlation with XF extracted from the nonlinear theory for all three classes of proteins. Therefore, this parameter can be used to predict XF for any protein, if its native structure is known.We studied the refolding free energy landscape of 26 proteins using the Go-like model. The distance between the denaturated state and the transition state, XF, was calculated using the Bell theory and the nonlinear Dudko-Hummer-Szabo theory, and its relation to the geometrical properties of the native state was considered in detail. We showed that none of the structural parameters, such as the contact order, protein length, and radius of cross section, correlate with XF for all classes of proteins. To overcome this problem, we have introduced the nematic order parameter P02, which describes the ordering of the structured elements of the native state. Due to its topologically global nature, P02 is better than other structural parameters in describing the folding free energy landscape. In particular, P02 displays a good correlation with XF extracted from the nonlinear theory for all three classes of proteins. Therefore, this parameter can be used to predict XF for any protein, if its native structure is known.