The Theory Of Biomolecular Conformational Change Upon Binding

It is very important to explore the dynamics and thermodynamic theory of biological process.As constrain of resolution of experiment,the exploration of biological process in molecular level is lacking.In this paper,based on the method of molecular dynamic simulation,we develop a systematic theory to explore the interesting and representative biological process which can't be captured by the experiment.Bridging between theory and experiment,the function of molecule can be uncovered in higher level.1.Calmodulin(CaM)is found to have the capability to bind multiple targets.Investigations on the association mechanism of CaM to its targets are crucial for understanding protein–protein binding and recognition.Here,we developed a structure-based model to explore the binding process between CaM and skMLCK binding peptide.We found the cooperation between nonnative electrostatic interaction and nonnative hydrophobic interaction plays an important role in nonspecific recognition between CaM and its target.We also found that the conserved hydrophobic anchors of skMLCK and binding patches of CaM are crucial for the transition from high affinity to high specificity.Furthermore,this association process involves simultaneously both local conformational change of CaM and global conformational changes of the skMLCK binding peptide.We found a landscape with a mixture of the atypical “induced fit,” the atypical “conformational selection,” and “simultaneously binding–folding,” depending on the synchronization of folding and binding.Finally,we extend our discussions on multispecific binding between CaM and its targets.These association characteristics proposed for CaM and skMLCK can provide insights into multispecific binding of CaM?2.Protein-DNA recognition is a central biological process that governs the life of cells.Here,we performed thermodynamic and kinetic simulations to explore the conformational transitions of DPO4 during binding to the target site in DNA by developing a structure-based model.Our results clearly showed that DPO4-DNA recognition involves 3D diffusion,then a short-range adjustment sliding on DNA and finally specific binding.The conformational changes in DPO4 happen throughout the binding process,with different stages representing different conformational distributions.The conformational dynamics in DPO4 seem to be fine-tuned by DNA.Meanwhile the different conformations of DPO4 have different effects on the DNA binding kinetics.We also found that electrostatic interactions on one hand facilitate the 3D diffusion as “steering forces”,and on the other hand hinder short-range sliding on DNA due to formation of non-native kinetic traps.The efficiency of specific DPO4-DNA recognition is determined by the interplay between multiple binding stages.In particular,we point out that the flexibility of the positively charged linker not only contributes to the conformational distribution in DPO4,but is also responsible for the stabilization of the non-specific complex,and is therefore critical for DPO4-DNA recognition.Our methods,with explicit consideration of the non-specific and specific interactions between DPO4 and DNA,provide a detailed description of the process of DPO4 binding to its target DNA.This work illustrates the process of specific protein-DNA recognition and the accompanying conformational dynamics,and thus enriches our understanding of the catalytic mechanism of DNA polymerization.