Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

Abstract

Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results.

Homologous ligands accommodated by discrete conformations of a buried cavity

“…This study suggests that relatively large, discrete changes in protein conformation to small ligand perturbation may be common. Anticipating such changes may demand long molecular dynamics simulations (10,(45)(46)(47)(48) or approaches that sample among precalculated states (49,50). The low energy of these states would also support a combination of experimental observation, such as NMR or crystallographic refinement, with computational modeling of protein conformational changes in ligand optimization (31,51).…”

Structure-Encoded Global Motions and Their Role in Mediating Protein-Substrate Interactions

“…Transmembrane (TM) helical segments TM1a-b, TM6a-b, and TM10 that line the binding cavity, exhibit significant structural rearrangements. (D) Global structural differences between LeuT in OFo state before substrate binding (dark orange), OFc state after substrate binding (yellow), and inward-facing open (IFo) state (blue) after substrate release to the intracellular (IC) medium (24) (E) Global structural changes observed in ENM-based simulations of OFo 4 IFo transition (28). TM1b-TM10, TM6a-TM10, and TM1a-TM6b center-of-mass (COM) distances serve as metrics for probing the extent of reconfiguration.…”

Computational characterization of structural dynamics underlying function in active membrane transporters

“…For instance, implicit membrane simulations (49) and coarse-grained models such as mixed elastic network models (mENM) (50), two-state anisotropic network models (51) and GŌ-like models (52) have been used to probe the OF-IF transition of transporters, often accompanied with the use of an enhanced sampling method such as dynamic importance sampling (DIMS) (53, 54), weighted ensemble (WE) path-sampling (52), and self-guided Langevin dynamics (SGLD) (49). The predicted transition pathways obtained from simplified models are sometimes converted into full-atomic representations and analyzed using all-atom unbiased MD simulations launched from the intermediates (50, 51, 53). …”

“…Employing DIMS and implicit solvent models, simulations suggest an intricate coupling between two flexible gates during the transition, rather than a simple rigid-body motion for LacY (53). The two-state anisotropic network model has been employed to construct the transition pathway of Glt Ph (51). Only using a few low frequency normal modes, this study was able to describe the entire transition as a rigid-body motion of the transport domain relative to the trimerization domain, followed by intra-domain rearrangements (51).…”