Application of Coarse-Grained (CG) Models to Explore Conformational Pathway of Large-Scale Protein Machines

Abstract

Protein machines are clusters of protein assemblies that function in order to control the transfer of matter and energy in cells. For a specific protein machine, its working mechanisms are not only determined by the static crystal structures, but also related to the conformational transition dynamics and the corresponding energy profiles. With the rapid development of crystallographic techniques, the spatial scale of resolved structures is reaching up to thousands of residues, and the concomitant conformational changes become more and more complicated, posing a great challenge for computational biology research. Previously, a coarse-grained (CG) model aiming at conformational free energy evaluation was developed and showed excellent ability to reproduce the energy profiles by accurate electrostatic interaction calculations. In this study, we extended the application of the CG model to a series of large-scale protein machine systems. The spike protein trimer of SARS-CoV-2, ATP citrate lyase (ACLY) tetramer, and P4-ATPases systems were carefully studied and discussed as examples. It is indicated that the CG model is effective to depict the energy profiles of the conformational pathway between two endpoint structures, especially for large-scale systems. Both the energy change and energy barrier between endpoint structures provide reasonable mechanism explanations for the associated biological processes, including the opening of receptor binding domain (RBD) of spike protein, the phospholipid transportation of P4-ATPase, and the loop translocation of ACLY. Taken together, the CG model provides a suitable alternative in mechanistic studies related to conformational change in large-scale protein machines.

The Nature of Functional Features of Different Classes of G-Protein-Coupled Receptors

“…The structures modeled in this study all followed the workflow we reported previously [ 20 ]. First, the structures of the inactive, intermediate, and active states were extracted from corresponding experimental structures, which were as follows: β 2AR-inactive (PDB ID: 6EG8), β 2AR-intermediate (PDB ID: 6E67), β 2AR-active (PDB ID: 3SN6), GCGR-partially active (PDB ID: 5YQZ), GCGR-fully active (PDB ID: 6WPW), mGluR2-inactive (PDB ID: 7EPA), and mGluR2-fully active (PDB ID: 7E9G).…”

“…The idea of such coarse-graining has become a common, well-accepted, and powerful strategy [ 16 ]. Here, we investigated the activation process of GPCRs using a coarse-grained (CG) model [ 17 , 18 , 19 , 20 ], which has been proven to be very effective in investigating many biophysical systems such as ATPase [ 21 , 22 ], SARS-CoV-2 spike [ 23 , 24 ], and GPCRs [ 25 , 26 , 27 ]. The CG strategies for a description of the functional properties focused on improving the electrostatic features of the model [ 17 ] and were refined for the treatment of membrane proteins [ 18 ].…”

“…The CG strategies for a description of the functional properties focused on improving the electrostatic features of the model [ 17 ] and were refined for the treatment of membrane proteins [ 18 ]. Moreover, the CG model has been shown to be applicable in mechanistic studies related to conformational changes in large-scale protein machines [ 20 ].…”

Mechanism Study of Proteins under Membrane Environment

“…It should be noted that, the treatment of electrostatic effects in this CG model is a key factor in clearly explaining the energetics in many complicated and large biological systems [ 19 , 27 , 28 ]. It is computed as a sum of the change in free energy associated with charge–charge interactions between ionizable side chains.…”