Showing papers on "Salt bridge (protein and supramolecular) published in 2016"

Computational investigation of cold denaturation in the Trp-cage miniprotein

Abstract: The functional native states of globular proteins become unstable at low temperatures, resulting in cold unfolding and impairment of normal biological function. Fundamental understanding of this phenomenon is essential to rationalizing the evolution of freeze-tolerant organisms and developing improved strategies for long-term preservation of biological materials. We present fully atomistic simulations of cold denaturation of an α-helical protein, the widely studied Trp-cage miniprotein. In contrast to the significant destabilization of the folded structure at high temperatures, Trp-cage cold denatures at 210 K into a compact, partially folded state; major elements of the secondary structure, including the α-helix, are conserved, but the salt bridge between aspartic acid and arginine is lost. The stability of Trp-cage’s α-helix at low temperatures suggests a possible evolutionary explanation for the prevalence of such structures in antifreeze peptides produced by cold-weather species, such as Arctic char. Although the 310-helix is observed at cold conditions, its position is shifted toward Trp-cage’s C-terminus. This shift is accompanied by intrusion of water into Trp-cage’s interior and the hydration of buried hydrophobic residues. However, our calculations also show that the dominant contribution to the favorable energetics of low-temperature unfolding of Trp-cage comes from the hydration of hydrophilic residues.

Replica Exchange Molecular Dynamics Study of Dimerization in Prion Protein: Multiple Modes of Interaction and Stabilization

Abstract: The pathological forms of prions are known to be a result of misfolding, oligomerization, and aggregation of the cellular prion. While the mechanism of misfolding and aggregation in prions has been widely studied using both experimental and computational tools, the structural and energetic characterization of the dimer form have not garnered as much attention. On one hand dimerization can be the first step toward a nucleation-like pathway to aggregation, whereas on the other hand it may also increase the conformational stability preventing self-aggregation. In this work, we have used extensive all-atom replica exchange molecular dynamics simulations of both monomer and dimer forms of a mouse prion protein to understand the structural, dynamic, and thermodynamic stability of dimeric prion as compared to the monomeric form. We show that prion proteins can dimerize spontaneously being stabilized by hydrophobic interactions as well as intermolecular hydrogen bonding and salt bridge formation. We have computed the conformational free energy landscapes for both monomer and dimer forms to compare the thermodynamic stability and misfolding pathways. We observe large conformational heterogeneity among the various modes of interactions between the monomers and the strong intermolecular interactions may lead to as high as 20% β-content. The hydrophobic regions in helix-2, surrounding coil regions, terminal regions along with the natively present β-sheet region appear to actively participate in prion-prion intermolecular interactions. Dimerization seems to considerably suppress the inherent dynamic instability observed in monomeric prions, particularly because the regions of structural frustration constitute the dimer interface. Further, we demonstrate an interesting reversible coupling between the Q160-G131 interaction (which leads to inhibition of β-sheet extension) and the G131-V161 H-bond formation.

Response to chemical induced changes and their implication in yfdX proteins

Abstract: yfdX proteins occur in a large number of virulent bacteria. Recently we have shown that STY3178, a yfdX protein from Salmonella Typhi, exists in a trimeric state in solution which is capable of interacting with antibiotics, stable at elevated temperatures and undergoes reversible thermal unfolding. In this present study, we report the chemical response of STY3178. We monitor the stability of the protein in presence of chaotropes. It can regain the native-like structure from the chaotrope induced unfolded states. The structural stability of this protein is further studied in a wide pH range which reveals that the STY3178 trimer is stable in both acidic as well as basic media. We further show that the protein interacts with oxalate in vitro. Finally, we perform computational studies viz. modeling and molecular dynamics simulation to understand the stability of trimeric STY3178 over its monomer conformation. The conformational thermodynamic changes indicate that oligomerization induces stability via salt bridge interactions, present at the monomer interface.

Role of salt bridge formation in the conformation change of proteins

Abstract: The role of salt bridge formation is very crucial in the conformation change of the proteins. Our earlier work had also confirmed the presence of salt bridge formations on the conformation change of the proteins in particular Calmodulin (CaM) protein. In the present study we perform the simulations of this protein at different temperatures and observe a crucial role of salt bride formations on the conformation changes observed. Parallel clusters are used to perform these simulations using the facilities of Inter University Accelerator Centre (IUAC), New Delhi, India. The present study is performed using computational facilities having namd package installed on the parallel clusters. Parallelization of this molecular dynamics (MD) package significantly helps to improve the computational time of the simulation.