Folding Mechanisms Of Natural And Synthesized Macromolecules Studied By Computer Simulations

The reliable folding of proteins is a prerequisite for them to function robustly.Mis-folding can lead to protein aggregates that cause severe diseases,such as Alzheimer's disease.Studying the driving forces,structures,and kinetics of protein folding is key to understand the folding mechanisms.Here,we investigated the role of nonnative interactions on the folding of some proteins and the effects of the solvent quality and chain stiffness on the end-to-end contact kinetics of semiflexible polymers.The main contents include the following aspects:?1?Experimental studies indicate that the A39V/N53P/V55L Fyn SH3 domain folds from the unfolded state to the native state via a low-populated on-pathway intermediate,whereas the folding of the wildtype is two-state-like.To get insights into the biophysical basis of their different folding mechanisms,we used native-centric models with and without additional transferrable,sequence-dependent nonnative hydrophobic interactions to study the folding behaviors of the Fyn SH3 domain and its mutant.The pure native-centric model predicts that both the wildtype and the mutant fold in a two-state manner,without any detectable intermediate.However,in the simulated trajectories based on the model with sequence dependent nonnative hydrophobic interactions,a low populated on-pathway intermediate was identified for the mutant,but not for the wild type,although it is not sufficient to induce chevron rollover.In the modelling intermediate,the topology of strands ?₁ to ?₄ followed by the helix turn is native-like,while strand ?₅ is mostly unstructured,which is in good agreement with experiments.Meanwhile,the nonnative contacts in the intermediate overlapped largely with those identified experimentally and the average rmsd value of the modelling intermediate ensemble from the experimental intermediate structure by NMR is about 0.72???.Further investigation implies that different folding mechanisms between the wildtype and the mutant might arise from the distinction of the nonnative contact patterns at the transition states.In addition,we predicted that nonnative interactions led to deceleration or acceleration of the folding largely depending on whether they could destabilize or stabilize the transition state relative to the unfolded state.This study implies that the simple native-centric model augmented by sequence-dependent nonnative hydrophobic interactions should be useful in general to predict the folding of proteins with a low-populated intermediate.?2?Motivated by loop closure during protein folding and DNA packing,we systemically studied the effects of the solvent quality and chain stiffness on the thermodynamics and kinetics of the end-to-end contact formation for semiflexible polymer chains with reactive ends by Langevin dynamics simulations.In thermodynamics,a rich variety of products of the end-to-end contact have been discovered,such as loop,hairpin,toroid,and rodlike bundle,the populations of which are dependent on the solvent quality and chain stiffness.In kinetics,when the solvent quality becomes poorer,the first end-to-end contact rate k_c increases initially and then decreases for single semiflexible polymer chains.In good or poor solvents,the first end-to-end contact rate k_c decreases with increasing bending stiffness k_? monotonically.However,in very poor solvents,the dependence of the logarithm of the first end-to-end contact rate ln k_c on bending stiffness k_? exhibits erratic behavior,which stems from more rugged energy landscape due to the formation of intermediate state composed of rodlike bundles with two ends in separation.The change of solvent quality and chain stiffness can modulate the kinetic partitioning of pathways to form the end-to-end contact.The diagram of the specific types of pathways to form the end-to-end contact in terms of the solvent quality and bending stiffness has been plotted.The region in which the complex kinetic behavior of the end-to-end contact formation emerges can be identified from the diagram.For semiflexible chains,with increasing chain length N,the rate k_c increases initially and then decreases:in good solvents,the rate k_c exhibits a power-law relationship to chain length N with an exponent of ??-1.50? in the region of long chains,in good agreement with the value derived from the experiment in the asymptotic limit of large N;in poor solvents,the rate k_c is a significantly stronger chain length dependence than those observed in good solvents in the region of long chains due to frustration to form the end-to-end contact along a specific path,especially the scaling exponent between the rate k_c and chain length N is ??-3.62? for the case of polymer chains with k_?=4 at the solvent quality ?_ij=1,in accord with the value obtained from the experiments.