Probing Conformational Transition of TRPV5 Induced by Mechanical Force Using Coarse-Grained Molecular Dynamics.

Transient receptor potential vanilloid 5 (TRPV5) is a calcium-selective TRP channel that plays a crucial role in calcium homeostasis regulation. However, there are still many issues that need to be addressed, such as the specific conformational transition of TRPV5 and the specific functions of each structure in cation gating. Here, we build a model of the calcium ion transport protein from Xenopus oocytes in the presence of the lipid membrane and water molecules. Due to the activation process of ion channels are global and collective, coarse-grained molecular dynamics (CG-MD) simulations of the potential of mean force along the conformational transition pathway are performed. The CG-MD simulations show that the S6 helix plays a vital role in the TRPV5 conformational transition. Most importantly, these simulated trajectories indicate that the activation of ion channels happens before the extension and rotation of S6 helices, revealing that TRPV5 has a unique gating mechanism different from TRPV6. The present work demonstrates how the mechanical force acting on the S6 helix opens the TRPV5 channel gates. These results deepen our understanding of the TRPV5 gating mechanism.

Evaluation of Interactions between SARS-CoV-2 RBD and Full-Length ACE2 with Coarse-Grained Molecular Dynamics Simulations.

Compared to all-atom models, coarse-grained models enable the investigation of the dynamics of simulation systems on a much larger length scale and a longer time scale, which makes them suitable for studying macromolecular systems. Hence, in this work, we performed multiple µs-scale Martini coarse-grained molecular dynamics simulations to reveal the interaction details between SARS-CoV-2 RBD and full-length human ACE2. Besides, the key coarse-grained systems were backmapped into the corresponding all-atom system for the display of structural details. Our results indicated that the plier structure in two ends of the binding interface plays a key role in the binding process of SARS-CoV-2 RBD with ACE2. Furthermore, we also found that when there is no B0AT1 in the simulation system, the N-terminus of ACE2 is more likely to approach the cell membrane, which has a strong correlation with the subsequent fusion of the virus with the cell membrane. These binding details of SARS-CoV-2 RBD and the ACE2 protease domain (PD) as well as the membrane orientation thermodynamics can promote the development of therapeutic drugs and preventive vaccines against SARS-CoV-2.