Assessing the Performance of Traveling-salesman based Automated Path Searching (TAPS) on Complex Biomolecular Systems

• DOI: 10.1021/acs.jctc.1c00182
• Publication Date: 2021-07-16T19:27:31Z
• Authors: Kun Xi; Zhenquan Hu; Qiang Wu; Meihan Wei; Runtong Qian; Lizhe Zhu
• Keywords: Intuition

Though crucial for understanding the function of large biomolecular systems, locating minimum free energy paths (MFEPs) between their key conformational states is far from trivial due to high-dimensional nature. Most existing path-searching methods require a static collective variable space as input, encoding intuition or prior knowledge transition mechanism. Such information is, however, hardly available priori and expensive validate. To alleviate this issue, we have previously introduced Traveling-salesman based Automated Path Searching method (TAPS) demonstrated its efficiency on simple peptide systems. Having implemented parallel version method, here assess performance TAPS three realistic systems (tens hundreds residues) in explicit solvents. We show that successfully located MFEP ground/excited state T4 lysozyme L99A variant, consistent with previous findings. also helped identifying important role two polar contacts directing loop-in/loop-out mitogen-activated protein kinase (MEK1), which explained mutant experiments. Remarkably, at minimal cost 126 ns sampling, revealed Ltn40/Ltn10 lymphotactin needs no complete unfolding/refolding β-sheets five are sufficient stabilize various partially unfolded intermediates along MFEP. These results present general promising tool studying functional dynamics complex