Sampling large conformational transitions: adenylate kinase as a testing ground

Abstract

A fundamental problem in computational biophysics is to deduce the function of a protein from the structure. Many biological macromolecules such as enzymes, molecular motors, or membrane transport proteins perform their function by cycling between multiple conformational states. Understanding such conformational transitions, which typically occur on the millisecond to second time scale, is central to understanding protein function. Molecular dynamics (MD) computer simulations have become an important tool to connect molecular structure to function but equilibrium MD simulations are rarely able to sample on time scales longer than a few microseconds-orders of magnitudes shorter than the time scales of interest. A range of different simulation methods have been proposed to overcome this time-scale limitation. These include calculations of the free energy landscape and path sampling methods to directly sample transitions between known conformations. All these methods solve the problem to sample infrequently occupied but important regions of configuration space. Many path-sampling algorithms have been applied to the closed ↔ open transition of the enzyme adenylate kinase (AdK), which undergoes a large, clamshell-like conformational transition between an open and a closed state. Here we review approaches to sample macromolecular transitions through the lens of AdK. We focus our main discussion on the current state of knowledge-both from simulations and experiments-about the transition pathways of ligand-free AdK, its energy landscape, transition rates, and interactions with substrates. We conclude with a comparison of the discussed approaches with a view towards quantitative evaluation of path-sampling methods.

Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

“…Here pathway divergence, already evident from the PC1-2 distribution of experimental conformers, contains information about the sequence of movements in a multi-step complex landscape; unbiased MD from unbound forms (Supplementary Fig. 6c) also hints to differences in the preferred forward/reverse paths as suggested for some proteins1. However, when asymmetry is low, comparison with the FELs from MD rather suggests the equivalence of forward/reverse routes: in the three cases examined, they appear to delimit not different linear paths, but rather an area in the conformational landscape that overlaps with the lowest energy passage connecting the end-state basins.…”

Understanding Thermosensitive Transient Receptor Potential Channels as Versatile Polymodal Cellular Sensors

“…97 Importantly, enhanced sampling methods can be employed to obtain equilibrium properties over longer timescales, including conformation changes underlying channel gating. [98][99][100][101] MD-based methods also exist to compute thermodynamic information that may be useful to correlate experimental observables such as single channel conductance or thermodynamics with structural conformational changes. 102,103 Because TRP channels are temperature sensitive, temperature-based ensemble methods, such as temperature replica exchange (typically coupled with Hamiltonian exchange), are of particular interest.…”

Frustration-guided motion planning reveals conformational transitions in proteins

“…The transition of ADK has been extensively studied with different computational methods . Abundant experimentally determined intermediate structures make it a suitable test case for validation.…”