Inferring object properties from human interaction and transferring them to new motions

Humans regularly interact with their surrounding objects. Such interactions often result in strongly correlated motions between humans and the interacting objects. We thus ask: “Is it possible to infer object properties from skeletal motion alone, even without seeing the interacting object itself?” In this paper, we present a fine-grained action recognition method that learns to infer such latent object properties from human interaction motion alone. This inference allows us to disentangle the motion from the object property and transfer object properties to a given motion. We collected a large number of videos and 3D skeletal motions of performing actors using an inertial motion capture device. We analyzed similar actions and learned subtle differences between them to reveal latent properties of the interacting objects. In particular, we learned to identify the interacting object, by estimating its weight, or its spillability. Our results clearly demonstrate that motions and interacting objects are highly correlated and that related object latent properties can be inferred from 3D skeleton sequences alone, leading to new synthesis possibilities for motions involving human interaction. Our dataset is available at http://vcc.szu.edu.cn/research/2020/IT.html.

Weakening of Interaction Networks with Aging in Tip-Link Protein Induces Hearing Loss

Age-related hearing loss (ARHL) is a common condition in humans marking the gradual decrease in hearing with age. Perturbations in the tip-link protein cadherin-23 that absorbs the mechanical tension from sound and maintains the integrity of hearing is associated with ARHL. Here, in search of molecular origins for ARHL, we dissect the conformational behavior of cadherin-23 along with the mutant S47P that progresses the hearing-loss drastically. Using an array of experimental and computational approaches, we highlight a lower thermodynamic stability, significant weakening in the hydrogen-bond network and inter-residue correlations among β-strands, due to the S47P mutation. The loss in correlated motions translates to not only a remarkable two orders of magnitude slower folding in the mutant but also to a proportionately complex unfolding mechanism. We thus propose that loss in correlated motions within cadherin-23 with aging may trigger ARHL, a molecular feature that likely holds true for other disease-mutations in β-strand-rich proteins.

Transmission of allosteric response within the homotrimer of SARS-CoV-2 spike upon recognition of ACE2 receptor by the receptor-binding domain

The pathogenesis of novel SARS-CoV-2 virus initiates through recognition of ACE2 receptor (Angiotensin-converting enzyme 2) of the host cells by the receptor-binding domain (RBD) located at spikes of the virus. Following receptor-recognition, proteolytic cleavage between S1 and S2 subunits of the spike protein occurs with subsequent release of fusion peptide. Here, we report our study on allosteric communication within RBD that propagates the signal from ACE2-binding site towards allosteric site for the post-binding activation of proteolytic cleavage. Using MD simulations, we have demonstrated allosteric crosstalk within RBD in apo- and receptor-bound states where dynamic correlated motions and electrostatic energy perturbations contribute. While allostery, based on correlated motions, dominates inherent distal communication in apo-RBD, electrostatic energy perturbations determine favorable crosstalk within RBD upon binding to ACE2. Notably, allosteric path is constituted with evolutionarily conserved residues pointing towards their biological relevance. As revealed from recent structures, in the trimeric arrangement of spike, RBD of one copy interacts with S2 domain of another copy. Interestingly, the allosteric site identified is in direct contact (H-bonded) with a region in RBD that corresponds to the interacting region of RBD of one copy with S2 of another copy in trimeric constitution. Apparently, inter-monomer allosteric communication orchestrates concerted action of the trimer. Based on our results, we propose the allosteric loop of RBD as a potential drug target.

Dynamic nuclear structure emerges from chromatin crosslinks and motors

The cell nucleus houses the chromosomes, which are linked to a soft shell of lamin filaments. Experiments indicate that correlated chromosome dynamics and nuclear shape fluctuations arise from motor activity. To identify the physical mechanisms, we develop a model of an active, crosslinked Rouse chain bound to a polymeric shell. System-sized correlated motions occur but require both motor activity and crosslinks. Contractile motors, in particular, enhance chromosome dynamics by driving anomalous density fluctuations. Nuclear shape fluctuations depend on motor strength, crosslinking, and chromosome-lamina binding. Therefore, complex chromatin dynamics and nuclear shape emerge from a minimal, active chromosome-lamina system.

Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments

Tau forms intracellular insoluble aggregates as a neuropathological hallmark of Alzheimer’s disease. Tau is largely unstructured, which complicates the characterization of the tau aggregation process. Recent studies have demonstrated that tau samples two distinct conformational ensembles, each of which contains the soluble and aggregation-prone states of tau. A shift to populate the aggregation-prone ensemble may promote tau fibrillization. However, the mechanism of this ensemble transition remains elusive. In this study, we explored the conformational dynamics of a tau fragment by using paramagnetic relaxation enhancement (PRE) and interference (PRI) NMR experiments. The PRE correlation map showed that tau is composed of segments consisting of residues in correlated motions. Intriguingly, residues forming the β-structures in the heparin-induced tau filament coincide with residues in these segments, suggesting that each segment behaves as a structural unit in fibrillization. PRI data demonstrated that the P301L mutation exclusively alters the transiently formed tau structures by changing the short- and long-range correlated motions among residues. The transient conformations of P301L tau expose the amyloid motif PHF6 to promote tau self-aggregation. We propose the correlated motions among residues within tau determine the population sizes of the conformational ensembles, and perturbing the correlated motions populates the aggregation-prone form.

Computational Analysis of Dynamic Allostery and Control in the SARS-CoV-2 Main Protease

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has generated a global pandemic and no vaccine or antiviral drugs exist at the moment of writing. An attractive coronavirus drug target is the main protease (Mpro, also known as 3CLpro) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition which targets regions beyond the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an Elastic Network Model (ENM) of the SARS-CoV-2 Mpro homodimer protein and analyse the dynamics and thermodynamics of the main protease’s ENM. We found a rich and heterogeneous dynamical structure in the correlated motions, including allosterically correlated motions between the homodimeric protease’s active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site for control of the protease function. Our results suggest new dynamically-driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragmentbased binding screens. The results also provide new insight into the protein physics of fluctuation allostery and its underpinning dynamical structure.

Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras

ABSTRACTK-Ras is the most frequently mutated protein in human cancers. However, until very recently, its oncogenic mutants were viewed as undruggable. To develop inhibitors that directly target oncogenic K-Ras mutants, we need to understand both their mutant-specific and pan-mutant dynamics and conformations. Recently, we have investigated how the most frequently observed K-Ras mutation in cancer patients, G12D, changes its local dynamics and conformations1. Here, we extend our analysis to study and compare the local effects of other frequently observed oncogenic mutations, G12C, G12V, G13D and Q61H. For this purpose, we have performed Molecular Dynamics (MD) simulations of each mutant when active (GTP-bound) and inactive (GDP-bound), analyzed their trajectories, and compared how each mutant changes local residue conformations, inter-protein distance distributions, local flexibility and residue pair correlated motions. Our results reveal that in the four active oncogenic mutants we have studied, the α2 helix moves closer to the C-terminal of the α3 helix. However, P-loop mutations cause α3 helix to move away from Loop7, and only G12 mutations change the local conformational state populations of the protein. Furthermore, the motions of coupled residues are mutant-specific: G12 mutations lead to new negative correlations between residue motions, while Q61H destroys them. Overall, our findings on the local conformational states and protein dynamics of oncogenic K-Ras mutants can provide insights for both mutant-selective and pan-mutant targeted inhibition efforts.