The relationship between the molecular functions of proteins and their three-dimensional (3D) folds is one of the unanswered biological questions that has attracted extensive attention. Despite decades of research, protein folding continues to remain among the great challenges in biophysics.

Recently, the Markov state model (MSM) approach has emerged as an efficient solution and can be used to construct a statistical description of protein folding. MSMs utilize large-scale statistical sampling to construct a comprehensive model of folding, which has been demonstrated to yield quantitative agreement with experimental results. 

The C-terminal domain (CTD) of the bacterial transcription antiterminatorRfaH undergoes a dramatic all-α-helix to all-β-barrel transition when released from its N-terminal domain (NTD). Accordingly, this drastic conformational change enables RfaH to physically couple the transcription and translation processes in gene expression. To understand the mechanism behind this extraordinary structural transition, Dr. Jiang's research group constructed MSMs based on both biased and unbiased MD simulations of the all-αand all-β states of RfaH-CTD.

This approach overcomes the time scale limitation of conventional approaches for the investigation of complex conformational transitions, and the resultant MSM provides a detailed mesoscopic view of the transformation pathway. It is expect the current study to deepen the understanding of the refolding mechanism of RfaH-CTD, which can not only provide new insights into the physical process of protein folding and unfolding but also shed light on the functional interactions of other “transformer proteins”.  

This study has been recently published in “Journal of Chemical Theory and Computation” with Dr. Hualiang Jiang and Dr. Mingyue Zheng as corresponding authors, and it was supported by the Hi-TECH Research and Development Program of China, the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” and the National Natural Science Foundation of China.

Full text: http://pubs.acs.org/doi/pdf/10.1021/ct5002279