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

Abstract

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

DNA Deformation Exerted by Regulatory DNA-Binding Motifs in Human Alkyladenine DNA Glycosylase Promotes Base Flipping

“…We performed additional free-energy calculations to evaluate the energetic differences of the base-flipping process between 3MeA and A. We first derived a base extrusion trajectory for each base system using TMD simulations, then employed a recently developed theoretical method TAPS to search for MFEP assessed by multidimensional scaling (Figure S14, Table S1, and details in the paragraph of TAPS optimization in Supporting Information). , The resulting converged transition path was then employed for the following free-energy calculations using the US strategy along the PCV-s (Figure S15, Table S2, and details in the paragraph of free-energy calculations in Supporting Information for the generation of the initial base-flipping pathways, path optimization using TAPS, and free-energy calculations).…”

Identifying a Feasible Transition Pathway between Two Conformational States for a Protein

“…For a transition completed within a large sampling space, the location of MFEP is of central interest. Initiating from a predefined or guessed path generated using various sampling techniques, path optimization schemes usually approach the MFEP by expanding the sampling region, including the string method with drifting paths, the traveling-salesman based automated path searching (TAPS) , that sample conformations perpendicular to the reference path, as well as other path refining methods.…”

Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants

“…As a recently matured method, the travelling-salesman-based automated path-searching (TAPS) method can efficiently locate the minimum free-energy path (MFEP) for complex biomolecular systems [ 49 , 50 ]. Before performing the TAPS optimization, one needs to define the path collective variable (PCV) in a high-dimensional path [ 61 ] (see Equation (1)).…”

“…After that, the candidate nodes for the new path were reordered via a travelling-salesman scheme (solved by the Concorde package) [ 65 ] and adjusted by the insertion and deletion of path nodes to maintain the geometric resolution of the path (more details are provided in Figure S1 and Refs. [ 49 , 50 ]).…”

“…Recently, we developed an efficient path-searching method—the travelling-salesman-based automated path-searching (TAPS) method—which aims to efficiently locate high-dimensional minimum-free-energy paths (MFEPs) between two stable states of a biomolecular system at affordable cost [ 49 ]. The robustness and efficiency of this method have been demonstrated in a variety of complex systems, with sizes ranging from tens to hundreds of residues [ 50 , 51 ]. Though not directly providing kinetic mechanisms, the high-dimensional MFEP found by TAPS is sufficient in offering atomistic insights into the effect of a mutation on the dynamics of the protein.…”