Zinc-fingers, which widely exist in eukaryotic cell and play crucial roles in life processes, depend on the binding of zinc ion for their proper folding. To computationally study the zinc coupled folding of the zinc-fingers, charge transfer and metal induced protonation/deprotonation effects have to be considered. Here, by attempting to implicitly account for such effects in classical molecular dynamics and performing intensive simulations with explicit solvent for the peptides with and without zinc binding, we investigate the folding of the Cys 2 His 2 type zinc-finger motif and the coupling between the peptide folding and zinc binding. We find that zinc ion not only stabilizes the native structure, but also participates in the whole folding process. It binds to the peptide at early stage of folding, and directs or modulates the folding and stabilizations of the component β-hairpin and α-helix. Such a crucial role of zinc binding is mediated by the packing of the conserved hydrophobic residues. We also find that the packing of the hydrophobic residues and the coordination of the native ligands are coupled. Meanwhile, the processes of zinc binding, mis-ligation, ligand exchange and zinc induced secondary structure conversion, as well as the water behaviour, due to the involvement of zinc ion are characterized. Our results are in good agreement with related experimental observations, and provide significant insight into the general mechanisms of the metal-cofactor dependent protein folding and other metal induced conformational changes of biological importance.

3,4-Dihydroxyphenylalanine (DOPA) is the noncanonical amino acid widely found in mussel holdfast proteins, which is proposed to be responsible for their strong wet adhesion. This feature has also inspired the successful development of a range of DOPA-containing synthetic polymers for wet adhesions and surface coating. Despite the increasing applications of DOPA in material science, the underlying mechanism of DOPA-wet surface interactions remains unclear. In this work, we studied DOPA-surface interactions one bond at a time using atomic force microscope (AFM) based single molecule force spectroscopy. With our recently developed "multiple fishhook" protocol, we were able to perform high-throughput quantification of the binding strength of DOPA to various types of surfaces for the first time. We found that the dissociation forces between DOPA and nine different types of organic and inorganic surfaces are all in the range of 60-90 pN at a pulling speed of 1000 nm s(-1), suggesting the strong and versatile binding capability of DOPA to different types of surfaces. Moreover, by constructing the free energy landscape for the rupture events, we revealed several distinct binding modes between DOPA and different surfaces, which are directly related to the chemistry nature of the surfaces. These results explain the molecular origin of the versatile binding ability of DOPA. Moreover, we could quantitatively predict the relationship between DOPA contents and the binding strength based on the measured rupture kinetics. These serve as the bases for the quantitative prediction of the relationship between DOPA contents and adhesion strength to different wet surfaces, which is important for the design of novel DOPA based materials.

The folding process of trpzip2 beta-hairpin is studied by the replica exchange molecular dynamics (REMD) and normal MD simulations, aiming to understand the folding mechanism of this unique small, stable, and fast folder, as well as to reveal the general principles in the folding of beta-hairpins. According to our simulations, the TS ensemble is mainly characterized by a largely formed turn and the interaction between the inner pair of hydrophobic core residues. The folding is a zipping up of hydrogen bonds. However, the nascent turn has to be stabilized by the partially formed hydrophobic core to cross the TS. Thus our folding picture is in essence a blend of hydrogen bond-centric and hydrophobic core-centric mechanism. Our simulations provide a direct evidence for a very recent experiment (Du et al., Proc Natl Acad Sci USA 2004;101:15915-15920), which suggests that the turn formation is the rate-limiting step for beta-hairpin folding and the unfolding is mainly determined by the hydrophobic interactions. Besides, the relationship between hydrogen bond stabilities and their relative importance in folding are investigated. It is found that the hydrogen bonds with higher stabilities need not play more important roles in the folding process, and vice versa.