Modeling Protein Dynamics from Brownian Motions to Transcription Regulation

Protein factors and enzymes largely employ Brownian motions for movements along DNA. How to achieve biological regulations out of thermal motions are of high interest as we model the proteins from atomic to coarse-grained (CG) and from molecular dynamics (MD) to stochastic simulations. Notably, we have revealed recently at atomic-scale molecular diffusion of a small transcription factor (TF) domain protein with 1-bp spontaneous stepping along DNA. Extensive samplings and kinetic model construction further show that hydrogen bonding dynamics for synchronization at the protein-DNA interface are rate limiting and likely serve for sequence information detection. The protein 1D diffusional search along DNA can be trapped upon the protein reorientation on specific DNA sequences. CG-MD to stochastic dynamics modeling then suggest that the protein stepping size can vary from one to several bps depending on protein-DNA interactions or protein responses to DNA sequence patterns. The level of stochasticity in the protein diffusion can nevertheless be regulated e.g., by varying solution ionic concentrations. The corresponding protein diffusional free energy profiling along DNA can be constructed and the ruggedness of the profiling can be tuned. We additionally show that a dimeric TF protein coordinates its two DNA binding domains/regions to achieve ‘inchworm’ stepping on the DNA, and lowering the solution ionic concentration may trigger the dimer dissociation into monomers on DNA. By demonstrating similar Brownian motions for RNA polymerase translocation on DNA, we emphasize that the thermal fluctuations can be nicely employed by such an enzyme to respond sensitively to identities or energetic biases of incoming nucleotide substrates for “selective ratcheting” or transcription fidelity control.