Browsing by Author "Lin, Xingcheng"

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    Contact map dependence of a T-cell receptor binding repertoire
    (American Physical Society, 2022) Chau, Kevin Ng; George, Jason T.; Onuchic, José N.; Lin, Xingcheng; Levine, Herbert; Center for Theoretical Biological Physics
    The T-cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T-cell receptor (TCR) specific to non-self-antigens displayed as peptides bound to the major histocompatibility complex (pMHC). The understanding of the dynamics of the adaptive immune system at a repertoire level is complex, due to both the nuanced interaction of a TCR-pMHC pair and to the number of different possible TCR-pMHC pairings, making computationally exact solutions currently unfeasible. To gain some insight into this problem, we study an affinity-based model for TCR-pMHC binding in which a crystal structure is used to generate a distance-based contact map that weights the pairwise amino acid interactions. We find that the TCR-pMHC binding energy distribution strongly depends both on the number of contacts and the repeat structure allowed by the topology of the contact map of choice; this in turn influences T-cell recognition probability during negative selection, with higher variances leading to higher survival probabilities. In addition, we quantify the degree to which neoantigens with mutations in sites with higher contacts are recognized at a higher rate.
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    Lowered pH Leads to Fusion Peptide Release and a Highly Dynamic Intermediate of Influenza Hemagglutinin
    (American Chemical Society, 2016) Lin, Xingcheng; Noel, Jeffrey K.; Wang, Qinghua; Ma, Jianpeng; Onuchic, José Nelson; Bioengineering; Biosciences; Chemistry; Physics and Astronomy; Center for Theoretical Biological Physics
    Hemagglutinin (HA), the membrane-bound fusion protein of the influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, we employed explicit-solvent molecular dynamics simulations to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt bridge between the N-terminus and Asp1122 of HA stem domain locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order–disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence of a long-lived asymmetric or “symmetry-broken” intermediate during the HA conformational change. This intermediate conformation is consistent with models of hemifusion, and its early formation during the conformational change has implications for the aggregation seen in HA activity.
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    RACER-m leverages structural features for sparse T cell specificity prediction
    (AAAS, 2024) Wang, Ailun; Lin, Xingcheng; Chau, Kevin Ng; Onuchic, José N.; Levine, Herbert; George, Jason T.; Center for Theoretical Biological Physics
    Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural information to overcome the need for extensive training sequence data, yet disentangling the heterogeneous TCR-antigen interface to accurately predict MHC-allele-restricted TCR-peptide interactions has remained challenging. Here, we present RACER-m, a coarse-grained structural model leveraging key biophysical information from the diversity of publicly available TCR-antigen crystal structures. Explicit inclusion of structural content substantially reduces the required number of training examples and maintains reliable predictions of TCR-recognition specificity and sensitivity across diverse biological contexts. Our model capably identifies biophysically meaningful point-mutant peptides that affect binding affinity, distinguishing its ability in predicting TCR specificity of point-mutants from alternative sequence-based methods. Its application is broadly applicable to studies involving both closely related and structurally diverse TCR-peptide pairs.
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    Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level
    (MDPI, 2019) Lin, Xingcheng; Kulkarni, Prakash; Bocci, Federico; Schafer, Nicholas P.; Roy, Susmita; Tsai, Min-Yeh; He, Yanan; Chen, Yihong; Rajagopalan, Krithika; Mooney, Steven M.; Zeng, Yu; Weninger, Keith; Grishaev, Alex; Onuchic, José Nelson; Levine, Herbert; Wolynes, Peter G.; Salgia, Ravi; Rangarajan, Govindan; Uversky, Vladimir; Orban, John; Jolly, Mohit Kumar
    Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences.
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    Uncovering the Molecular Mechanism Underpinning the Function of Influenza Hemagglutinin
    (2018-04-19) Lin, Xingcheng; Onuchic, José N; Levine, Herbert; Clementi, Cecilia
    Influenza Hemagglutinin (HA) is a homotrimeric viral fusion protein critical for the invasion of flu viruses. It is composed of two domains, a receptor-binding domain called HA1 and a viral fusion stem domain called HA2. HA assists in the invasion of viruses through an HA2 induced membrane fusion process under a lowered pH environment. The crystal structures of HA2 before and after the membrane fusion were solved previously. A comparison between them reveals a dramatic structural rearrangement of HA2 during the viral invasion process. In spite of the solved structures, dynamic details about how this structural transition happens are still missing. This thesis focuses on the investigation of the molecular mechanism underlying this structural transition and understanding how this transition induces the subsequent membrane fusion process. In Chapter Two, we used a coarse-grained dual-basin structure-based model for investigating the overall structural transition of HA2. We find two disparate routes on this transition landscape and multiple metastable intermediates. Specifically, our simulations feature an early ``cracking'' process initializing the HA2 transition and a ``symmetry-breaking'' process leading to a functional bending structure of HA2. In Chapter Three, we employed detailed explicit-solvent simulations with transferrable force fields to probe the initial phase of HA2 transition. Specifically, we focused on the role of a lowered pH in the release of fusion peptides. Our results indicate that a buried salt bridge locks the fusion peptides in the pre-fusion structure, and the breaking of it is crucial for releasing fusion peptides and the subsequent HA2 transition. Further, our detailed simulations reproduce the cracking and symmetry-breaking processes as we observed in the simulations with the structure-based model. In Chapter Four, we focused on a loop-to-coiled-coil transition of the B-loop domain of HA2, which was presumed to be a critical step in the structural transition of HA2. We implemented explicit-solvent simulations together with enhanced sampling techniques and showed that the post-fusion state of the B-loop by itself is unstable. A buried hydrophilic residue, Thr59, is shown to cause the instability. A further study indicates that Thr59 is the only residue of the B-loop that strictly differentiates between two taxonomic groups of HAs. Our simulations support previous studies by showing that the functional motion of HA2 is dynamic. The slow transition of the B-loop allows for more degrees of freedom for choosing the transition pathways. Overall, our simulations indicate a dynamic motion of HAs in its functional transition, which encourages different pathways HAs utilized to induce the membrane fusion process.