Quantifying The Energy Landscape Of The Flexible Biomolecular Dynamics

Biomolecular dynamics is prevalent and fundamental in cellar activity.Biomolecular dynamics is often flexible and associated with large conformationalchanges. It has been recognized that the flexibility or conformational transition playsa major role in many biomolecular process, including protein folding, protein bindingand protein allostery. Biomolecules realize their function by binding to the partners.The conformational dynamics in binding is also critical for the biomolecular function.However, the physical and global understanding for the flexible biomoleculardynamics is still challenging. In this thesis, we meet this challenge by quantifying theenergy landscape topography and establishing the connections between theoreticalpredications and experiment measurements.1. We quantify the protein folding energy landscapes by exploring the density ofstates. We calculate three energy landscape topography quantities: energy gap, energyroughness and entropy, corresponding to the slope, bumpiness and size of the foldingfunnels, respectively. We show that the dimensionless ratio between gap, roughnessand entropy can accurately describe the energy landscape topography. We find that theenergy landscape topography can predict the folding thermodynamic stability againsttrapping and the kinetic rates. More funneled energy landscapes lead to more stablethermodynamics and faster kinetics. We investigate the role of topological andenergetic roughness for protein of different sizes and for protein of same size, but withdifferent structural topologies. We find that the monotonic correlations between theenergy landscape topography and folding thermodynamics as well as kinetics arepresent in all the cases. In short, we demonstrate that the folding energy landscape isthe underlying factor to determine the folding thermodynamics and kinetics. Thiswork bridges the gap between theories and experiments. 2. Using density of states, we quantify the effective binding and folding, as wellas the whole global binding-folding energy landscape topography in flexiblebiomolecular recognition for15homodimers. Based on the interplay betweentopography of the effective binding and folding energy landscape topography, the15homodimers can be successfully classified into two-state cooperative “coupledbinding-folding” and three-state non-cooperative “folding prior to binding” scenario.The results are consistent with the previous theoretical and experimentalinvestigations. We find that the non-native interactions modulate the associationmechanism through the underlying binding and folding energy landscapes. Byquantifying the whole global binding-folding energy landscapes, we find the strongcorrelation between the landscape topography measure and the thermodynamicstability versus trapping, as well as the kinetic rates. Therefore, we demonstrate thatenergy landscape determines the thermodynamics and kinetics of the flexiblebiomolecular recognition. We also find “U-shape” temperature-dependent kineticbehavior and a dynamical cross-over temperature of dividing exponential andnonexponential kinetics for two-state homodimers. The findings are controlled by thetopography of the underlying energy landscapes. Our results provide the quantitativebridge between the landscape topography and experimental measurements.3. By developing a structure-based coarse-grained model, in whichDebye-Hückel model is implemented for describing the electrostatic interactions, weinvestigate the histone chaperone Chz1binding to its target histone variantH2A.Z-H2B. Free Chz1is a typical Intrinsically Disordered Protein (IDP). We findthat the folding conformational changes in Chz1only happens after the majortransition states and then Chz1undergoes coupled binding-folding through twoparallel pathways. We find that the inter-chain electrostatic interactions serve as“steering forces” to facilitate the association. Interestingly, we find increasing thestrength of electrostatic interactions leads to decreasing rate of formation of the finalcomplex. It is due to that the strong intra-chain electrostatic interactions collapse theChz1into non-native compact structures. Binding is slowed by the escape of the trapson the energy landscapes. Our studies provide an ionic-strength-controlled flexible binding-folding mechanism. The findings lead to a cooperative binding mechanism of“local collapse or trapping” and “fly-casting” together and a new understanding of theroles of electrostatic interactions in IDPs’ binding.