Kinesin-microtubule interaction reveals the mechanism of kinesin-1 for discriminating the binding site on microtubule

Microtubule catalyzes the mechanochemical cycle of kinesin,a kind of molecular motor,through its crucial roles in kinesin's gating,ATPase and force-generation process.These functions of microtubule are realized through the kinesin-microtubule interaction.The binding site of kinesin on the microtubule surface is fixed.For most of the kinesin-family members,the binding site on microtubule is in the groove betweenα-tubulin andβ-tubulin in a protofilament.The mechanism of kinesin searching for the appropriate binding site on microtubule is still unclear.Using the molecular dynamics simulation method,we investigate the interactions between kinesin-1 and the different binding positions on microtubule.The key non-bonded interactions between the motor domain and tubulins in kinesin's different nucleotide-binding states are listed.The differences of the amino-acid sequences betweenα-andβ-tubulins make kinesin-1 binding to theα–βgroove much more favorable than to theβ–αgroove.From these results,a two-step mechanism of kinesin-1 to discriminate the correct binding site on microtubule is proposed.Most of the kinesin-family members have the conserved motor domain and bind to the same site on microtubule,the mechanism may also be shared by other family members of kinesin.

Oscillation of S5 helix under different temperatures in determination of the open probability of TRPV1 channel

Transient receptor potential vanilloid subtype 1 (TRPV1) is a polymodel sensory receptor and can be activated by moderate temperature (≥ 43 ℃). Though extensive researches on the heat-activation mechanism revealed some key elements that participate in the heat-sensation pathway, the detailed thermal-gating mechanism of TRPV1 is still unclear. We investigate the heat-activation process of TRPV1 channel using the molecular dynamics simulation method at different temperatures. It is found that the favored state of the supposed upper gate of TRPV1 cannot form constriction to ion permeation. Oscillation of S5 helix originated from thermal fluctuation and forming/breaking of two key hydrogen bonds can transmit to S6 helix through the hydrophobic contact between S5 and S6 helix. We propose that this is the pathway from heat sensor of TRPV1 to the opening of the lower gate. The heat-activation mechanism of TRPV1 presented in this work can help further functional study of TRPV1 channel.

Structural effects and competition mechanisms targeting the interactions between p53 and MDM2 for cancer therapy

Approximately half of all human cancers show normal TP53 gene expression but aberrant overexpres- sion of MDM2 and/or MDMX. This fact suggests a promising cancer therapeutic strategy in targeting the interactions between p53 and MDM2/MDMX. To help realize the goal of developing effective in- hibitors to disrupt the p53-MDM2/MDMX interaction, we systematically investigated the structural and interaction characteristics of p53 with inhibitors of its interactions with MDM2 and MDMX from an atomistic perspective using stochastic molecular dynamics simulations. We found that some spe- cific a helices in the structures of MDM2 and MDMX play key roles in their binding to inhibitors, and that the hydrogen bond formed by the Trp23 residue of p53 with its counterpart in MDM2 or MDMX determines the dynamic competition processes of the disruption of the MDM2-p53 interaction and replacement of p53 from the MDM2-p53 complex in vivo. The results reported in this paper are expected to provide basic information for designing functional inhibitors and realizing new strategies of cancer gene therapy.