permutation on the protein chain can give important information about the connectivity, structure and folding or unfolding kinetics which guides its translocation and subsequent function in the cell. To study the process of cotranslocational unfolding and its dependence on the secondary structure at the N-terminus of the protein imported, we conduct a comparative molecular dynamics study of circular permutants of Dihydrofolate reductase(DHFR) using atomistic model in CHARMM. Six Circular Permutants -CP25, CP38, CP78, CP97, CP108, CP133 -are generated such that the new N-terminus leads either to an alpha helix or a beta-strand. using Steered Molecular Dynamics we compute the work distributions for the forced unfolding of each of the CP's and native DHFR using two processes -unfolding through the geometrical constriction of the model pore as in mitochondrial translocation and mechanical unfolding with the C-terminus fixed. In both cases the unfolding force is applied at the N-terminus. A comparison of the free energy profile along the reaction coordinate for each circular permutant can lead to identification of different unfolding pathways and hence import efficiency based on first resistant structure adjacent to the targeting sequence. 2053-Pos Board B72Design of Structral Metal Sites in Heterospecific Collagen Peptides Avanish S. Parmar, Fei Xu, Douglas pike, Vikas Nanda. UMDNJ, Piscataway, NJ, USA. Globular proteins commonly use structural metals to promote folding and enhance stability. There are no good examples of similar metal utilization in fibrillar proteins such as collagen. We hypothesized a metal binding site at the end of an A:B:C-type collagen triple helix could be designed to enhance folding and stability without compromising specificity. A heterospecific metal binding site was computationally designed by sampling backbone and sidechain conformations of C-terminal amino acids of the triple helix to optimize metal site geometry. Experimental characterization of the designed sequences confirms that zinc-binding enhances structure and thermal stability of the A:B:C heterotrimer peptides under physiological buffer conditions. By varying metal concentration, it is possible to study the relative contributions of electrostatic interactions and metal binding, to triple helix stability and structure. Metal-directed switching of triple helical structure has potential applications in self-assembly of higher order biomaterials, translational regenerative medicine and drug design. 2054-Pos Board B73Aromatic Amino Acids Confer Folding Propensities to a Nine-Residue Peptide We investigated how individual amino acids affect the structural propensities of short peptides. We based our work on NMR measurements of peptides of sequence EGAAXAASS, where 15 different amino acids were tested at position X. Here we focus on the two peptides with X = Trp and Gly, especially on their residual dipolar couplings (RDC). The pattern of the peptide with X = Gly was rather flat, suggesting an extended or unfolded peptide, while the ...
Protein fitness studied is a generic form of fitness costs due to misfolded proteins; s = k exp(DG / kT) ( 1 -exp(DDG / kT)), where s and DDG are selective advantage and stability change of a mutant protein, DG is the folding free energy of the wild-type protein, and k is a parameter representing protein abundance and indispensability. The distribution of DDG is approximated to be a bi-Gaussian distribution, which represents structurally slightly-or highly-constrained sites. Also, the mean of the distribution is negatively proportional to DG. The evolution of this gene has an equilibrium point DGe, the range of which is consistent with observed values in the ProTherm database. The probability distribution of Ka/Ks, the ratio of nonsynonymous to synonymous substitution rate per site, over fixed mutants in the vicinity of the equilibrium shows that nearly neutral selection is predominant only in low-abundant, non-essential proteins of DGe > À2.5 kcal/mol. In the other proteins, positive selection on stabilizing mutations is significant to maintain protein stability at equilibrium as well as random drift on slightly negative mutations, although the average is less than 1. Slow evolutionary rates can be caused by high protein abundance/indispensability and large effective population size, which produce positive shifts of DDG through decreasing DGe, and by strong structural constraints, which directly make DDG more positive. Protein abundance/indispensability more affect evolutionary rate for less constrained proteins, and structural constraint for less abundant, less essential proteins.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.