Abstract
Free energy calculations of the potential of mean force (PMF) based on the combination of targeted molecular dynamics (TMD) simulations and umbrella samplings as a function of physical coordinates have been applied to explore the detailed pathways and the corresponding free energy profiles for the conformational transition processes of the butane molecule and the 35-residue villin headpiece subdomain (HP35). The accurate PMF profiles for describing the dihedral rotation of butane under both coordinates of dihedral rotation and root mean square deviation (RMSD) variation were obtained based on the different umbrella samplings from the same TMD simulations. The initial structures for the umbrella samplings can be conveniently selected from the TMD trajectories. For the application of this computational method in the unfolding process of the HP35 protein, the PMF calculation along with the coordinate of the radius of gyration (Rg) presents the gradual increase of free energies by about 1 kcal/mol with the energy fluctuations. The feature of conformational transition for the unfolding process of the HP35 protein shows that the spherical structure extends and the middle α-helix unfolds firstly, followed by the unfolding of other α-helices. The computational method for the PMF calculations based on the combination of TMD simulations and umbrella samplings provided a valuable strategy in investigating detailed conformational transition pathways for other allosteric processes.
Highlights
It is well known that the characterization of the structure and the energetics of allostery for biological systems play a crucial role in understanding biological functions of cell signaling and metabolism regulation [1,2,3,4,5]
It is demonstrated in this method that the targeted molecular dynamics (TMD) simulation can provide the obvious images of large-scale conformational transitions that are applied to selection of initial structures of umbrella samplings for potential of mean force (PMF) calculations
For the dihedral coordinate of180 ̋ to 180 ̋, based on the umbrella sampling windows selected from three individual TMD simulations, the 19 sampling data from the sum of all sampling windows were used for the PMF calculation
Summary
It is well known that the characterization of the structure and the energetics of allostery for biological systems play a crucial role in understanding biological functions of cell signaling and metabolism regulation [1,2,3,4,5]. The detailed discussion of such method for calculating possible pathways and the accurate free energy variations will be valuable for activating the research field of large-scale conformational transitions of biologic systems. Our main objectives were (1) to address the accuracy of PMF calculations for a rotation transition process of a typical butane molecule based on the same TMD simulation and different umbrella samplings under two transition coordinates of dihedral rotation and RMSD variation; (2) to investigate feasibility of the combination of TMD simulation and umbrella samplings to select initial structures of sampling simulations; (3) to explore the application of this method on the unfolding transition of the 35-residue subdomain of the villin headpiece (HP35) [58,59]
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