Buyong Ma

Leidos Biomedical Research, Inc. National Cancer Institute, NIH · Basic Science Program

All soluble proteins populate conformational ensembles that together constitute the native state. Their fluctuations in water are intrinsic thermodynamic phenomena, and the distributions of the states on the energy landscape are determined by statistical thermodynamics; however, they are optimized to perform their biological functions. In this revi...

How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the membranes using computational approaches. Here, we investigat...

Alzheimers' disease (AD) is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapy is a promising approach; but amyloidantibody structural information is limited. Here we simulate the recognition of monomeric, oligomeric, and fibril Aβ by three homologous antibodies (solanezumab, crenezumab, and their chim...

A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core h...

Proper organization of intracellular assemblies is fundamental for efficient promotion of biochemical processes and optimal assembly functionality. Although advances in imaging technologies have shed light on how the centrosome is organized, how its constituent proteins are coherently architected to elicit downstream events remains poorly understoo...

RNA flexibility is reflected in its heterogeneous conformation. Through direct visualization using atomic force microscopy (AFM) and the adenosylcobalamin riboswitch aptamer domain as an example, we show that a single RNA sequence folds into conformationally and architecturally heterogeneous structures under near-physiological solution conditions....

Over the past decade, Markov State Models (MSM) have emerged as powerful methodologies to build discrete models of dynamics over structures obtained from Molecular Dynamics trajectories. The identification of macrostates for the MSM is a central decision that impacts the quality of the MSM but depends on both the selected representation of a struct...

RNA flexibility is reflected in its heterogeneous conformation. Existing techniques, such as NMR, crystallography, or cryo-EM, are not suited for studying highly heterogeneous conformation. Through direct visualization using atomic force microscopy (AFM) and the adenosylcobalamin riboswitch aptamer domain as an example, we show that a single RNA se...

The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC developm...

RNA-binding motif 38 (RBM38) is a member of a protein family with a highly conserved RNA-binding motif and has been shown to regulate mRNA processing, stability, and translation. Survivin is an essential modulator of apoptotic and nonapoptotic cell death as well as a stress responder. Survivin mRNA is the fourth most frequently overexpressed transc...

T cells are vital for adaptive immune responses that protect against pathogens and cancers. The T cell receptor (TCR)–CD3 complex comprises a diverse αβ TCR heterodimer in noncovalent association with three invariant CD3 dimers. The TCR is responsible for recognizing antigenic peptides bound to MHC molecules (pMHC), while the CD3 dimers relay activ...

Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapies using antibodies to lower assembled Aβ provide a promising approach and have been widely studied. Anti-amyloid antibodies are often selective to amyloid conformation, and the lack of amyloid-antibody structural information...

Z basic -ΔI-CM is a novel intein-based self-cleavable tag we developed to accelerate the soluble expression of recombinant proteins in Escherichia coli (E. coli). Previously we found that intein activity could be interfered by its flanking exteins, and thus reducing the production efficiency and final yield. In this work, we used CXC-chemokine 9 (C...

The mechanism whereby αβ T cell receptor (TCR) engagement by peptide–MHC (pMHC) is first communicated to the CD3 signaling apparatus of the TCR–CD3 complex, a process termed early T cell activation, is not well understood. To address the possibility that pMHC binding induces allosteric changes in TCR conformation and/or dynamics that are relayed to...

About 20% of the cancer incidences worldwide have been estimated to be associated with infections. However, the molecular mechanisms of exactly how they contribute to host tumorigenesis are still unknown. To evade host defense, pathogens hijack host proteins at different levels: sequence, structure, motif, and binding surface, i.e., interface. Inte...

Rbm38 is a p53 target and an RNA-binding protein known to suppress p53 translation by preventing eukaryotic translation initiation factor 4E (eIF4E) from binding to p53 mRNA. In this study, we show that synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E, including an 8 amino acid peptide (Pep8) derived from Rbm38, are...

p53 is a tumor suppressor protein that maintains genome stability, but its Δ133p53β and Δ160p53β isoforms promote breast cancer cell invasion. The sequence truncations in the p53 core domain raise key questions related to their physicochemical properties, including structural stabilities, interaction mechanisms, and DNA‐binding abilities. Herein, w...

The Ras superfamily of GTPases is a family of binary molecular switches that regulate a variety of cellular processes, such as proliferation and morphological control. Many members of the Ras superfamily are localized to membrane environments and interact with a variety of effectors to promote unique signaling consequences. Due to the strong correl...

The intracellular deposition of fibrils composed of the microtubule-associated protein Tau is a characteristic feature of Alzheimer's disease (AD) and other fatal neurodegenerative disorders collectively known as tauopathies. Short Tau fibrils spread intracerebrally through transfer between interconnected neurons. Once taken up by a recipient cell,...

T cells generate adaptive immune responses mediated by the T cell receptor (TCR)-CD3 complex comprising an αβ TCR heterodimer non-covalently associated with three CD3 dimers. In early T cell activation, αβ TCR engagement by peptide-major histocompatibility complex (pMHC) is first communicated to the CD3 signaling apparatus of the TCR-CD3 complex, b...

Aβ is the toxic amyloid polypeptide responsible for Alzheimer’s disease (AD). Prevention and elimination of the Aβ misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the Aβ-Specific Single-domain (VH) antibody, recognizes Aβ aggregates with high affinity and specificity and reduces their toxicities. Empl...

Npu DnaE is a naturally occurred split intein possessing robust trans-splicing activity and could be engineered to perform rapid C-terminal cleavage module by a single mutation D118G. Unfortunately, however, for this modified selfcleaving module, reducing agents were needed to trigger the rapid cleavage, which prevents the utilization in purificati...

Antibody therapies with high efficiency and low toxicity are becoming one of the major approaches in antibody therapeutics. Based on high-throughput sequencing and increasing experimental structures of antibodies/antibody-antigen complexes, computational approaches can predict antibody/antigen structures, engineering the function of antibodies and...

Protein aggregation is associated with many human diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and type II diabetes (T2D). Understanding the molecular mechanism of protein aggregation is essential for therapy development. Molecular dynamics (MD) simulations have been shown as powerful tools to study protein aggregation. Howe...

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are two common protein aggregation diseases. Compelling evidence has shown a link between AD and T2D, which may derive from interspecies cross-sequence interactions between amyloid-β peptide (Aβ), associated with AD, and human islet amyloid polypeptide (hIAPP), associated with T2D. Herein, we prese...

The tau fibrillar structures from the brain of an Alzheimer’s patient have a core with C-shaped motif of third and fourth repeat domains (R3-R4). Our simulations indicated that the C-shaped...

The pathology of type 2 diabetes mellitus is associated with the aggregation of human islet amyloid polypeptide (hIAPP) and aggregation-mediated membrane disruption. The interactions of hIAPP aggregates with lipid membrane, as well as the effects of pH and lipid composition at the atomic level, remain elusive. Herein, using molecular dynamics simul...

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs...

Computational prediction and design of membrane protein–protein interactions facilitate biomedical engineering and biotechnological applications. Due to their antimicrobial activity, human defensins play an important role in the innate immune system. Human defensins are attractive pharmaceutical targets due to their small size, broad activity spect...

s Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the κ light-chain is dominant (λ/κ = 1:2) in healthy individuals, λ is highly overrepresented (λ/κ = 3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We e...

A critical application of inteins has been the development of self-cleaving affinity tags for protein purification. In these applications, the inteins are modified to exhibit isolated cleaving of the intein-extein bonds at either their N- or C-terminus, or both. By replacing one extein with an affinity tag, and the other extein with a desired targe...

Deciphering antibody-protein antigen recognition is of fundamental and practical significance. We constructed an antibody structural dataset, partitioned it into human and murine subgroups, and compared it with nonantibody protein-protein complexes. We investigated the physicochemical properties of regions on and away from the antibody-antigen inte...

There is a strong correlation between some pathogens and certain cancer types. One example is Helicobacter pylori and gastric cancer. Exactly how they contribute to host tumorigenesis is however a mystery. Pathogens often interact with the host through proteins. To subvert defense, they may mimic host proteins at the sequence, structure, motif or i...

Alzheimer’s disease (AD), a common neurodegenerative disease, is characterized by the aggregation of amyloid-β (Aβ) peptides. The interactions of Aβ with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the Aβ-lipid interactions and how these in...

Host defense peptides (HDPs) feature evolution-tested potency against life-threatening pathogens. While piscidin 1 (p1) and piscidin 3 (p3) are homologous and potent fish HDPs, only p1 is strongly membranolytic. Here, we hypothesize that another mechanism imparts p3 strong potency. We demonstrate that the N-termini of both peptides coordinate Cu(2+...

How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on the residue-residue distances detected experimentally for Bax and its homologous protein (Bak), we recently computationally solve the first atomic model for Bax oligomeric pores at the m...

The pathogenesis of Parkinson’s disease is closely associated with the aggregation of the α-synuclein protein. Several familial mutants have been identified and shown to affect the aggregation kinetics of α-synuclein through distinct molecular mechanisms. Quantitative evaluation of the relative stabilities of the wild type and mutant fibrils is cru...

pH is highly regulated in the mammalian central nervous systems. Neuronal calcium sensor-1 (NCS-1) can interact with numerous target proteins. Compared with C. elegans, evolution has avoided histidine residues at positions 102 and 83 in the human and Xenopus laevis NCS-1 protein, possibly to decrease conformational sensitivity to pH gradients in sy...

Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed molecular dynamics (MD) simulations of the complex...

The mechanisms by which proteins evolve new functions can be slow and mysterious. Comprehensive structural analysis of enzyme variants reveal how gradual enrichments of pre-existing populations with the right productive dynamics for new functions can accomplish this aim.

The abnormal accumulation and aggregation of amyloid β (Aβ) is one of the key factors of the synaptic impairment in Alzheimer's disease. Biomolecules, e.g., apolipoproteins, and membrane receptors, are implicated in the aggregation and toxicity of Aβ. Engineered molecules, such as enzymes, antibodies, and nanoparticles, are designed to interfere wi...

Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy me...

MyD88 is an essential adaptor protein, which mediates the signaling of the toll-like and interleukin-1 receptors’ superfamily. The MyD88 L252P (L265P) mutation has been identified in diffuse large B-cell lymphoma. The identification of this mutation has been a major advance in the diagnosis of patients with aldenstrom macroglobulinemia and related...

Background: The dominant feature in neurodegenerative diseases is protein aggregations that lead to neuronal loss. Immunotherapies using antibodies or antibody fragments to target the aggregations are a highly perused approach. The molecular mechanisms underlying the amyloid-based immunotherapy are complex. Deciphering the properties of amyloidoge...

Investigation of macromolecular structure and dynamics is fundamental to understanding how macromolecules carry out their functions in the cell. Significant advances have been made toward this end in silico, with a growing number of computational methods proposed yearly to study and simulate various aspects of macromolecular structure and dynamics....

Abbreviations in alphabetical order. Abbreviations are provided for names of methods and proteins. (PDF)

Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. Herein, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used t...

Neuronal calcium sensor-1 (NCS-1) protein has orthologues from Saccharomyces cerevisiae to human with highly conserved amino acid sequences. NCS-1 is an important factor controlling the animal's response to temperature change. This leads us to investigate the temperature effects on the conformational dynamics of human NCS-1 at 310 and 316 K by all-...

Recent studies suggested that p53 aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, with adverse cancer consequences. The p53 aggregation-nucleating 251ILTIITL257 fragment is a key segment in wild-type p53 aggregation; however, an I254R mutation can prevent it. It was suggested that self-asse...

Tau proteins are hyperphosphorylated at common sites in the N- and C- terminal domains in at least three neurodegenerative diseases, Parkinson, dementia with Lewy bodies and Alzheimer's, suggesting specific pathology but general mechanism. Full-length human tau filament comprises a rigid core and a two-layered fuzzy coat. Tau is categorized into tw...

Intrinsically disordered protein (IDP) of tau binds and stabilizes microtubule, which contributes to the proper function of neuron, while its aggregation is implicated in Alzheimer's disease. In recent years, we have conducted various extensive molecular dynamics simulations of tau proteins in their monomer, normal fibril, and hyper-phosphorylated...

The aggregation of the copper-zinc superoxide dismutase (SOD1) protein is linked to familial amyotrophic lateral sclerosis, a progressive neurodegenerative disease. A recent experimental study has shown that the 147GVIGIAQ153 SOD1 C-terminal segment not only forms amyloid fibrils in isolation but also accelerates the aggregation of full-length SOD1...

The aggregates of α-synuclein (αS) are a major pathological hallmark of Parkinson’s disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the αS aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available expe...

Immobilized ions modulate nearby hydrophobic interactions and influence molecular recognition and self-assembly. We simulated disulfide bond-locked double mutants (L17C/L34C) and observed allosteric modulation of the peptide's intra-molecular interactions by the N-terminal tail. We revealed that the non-contacting charged N-terminal residues help t...

Unlabelled: HIV-1 immature particle (virus-like particle [VLP]) assembly is mediated largely by interactions between the capsid (CA) domains of Gag molecules but is facilitated by binding of the nucleocapsid (NC) domain to nucleic acid. We previously investigated the role of SP1, a "spacer" between CA and NC, in VLP assembly. We found that small c...

Neuronal calcium sensor-1 (NCS-1) protein has been implicated in multiple neuronal functions by binding partners mostly through a largely exposed hydrophobic crevice (HC). In the absence of a ligand, the C-terminal tail (loop L3, residues D176~V190) binds directly to the HC pocket as a ligand mimetic, occupying the HC and regulating its conformatio...

Clinical studies have identified Type 2 diabetes (T2D) as a risk factor of Alzheimer's disease (AD). One of the potential mechanisms that link T2D and AD is the loss of cells associated with degenerative changes. Amylin1-37 aggregates (the pathological species in T2D) were found to be co-localized with those of Aβ1-42 (the pathological species in A...

An important goal in molecular biology is to understand functional changes upon single-point mutations in proteins. Doing so through a detailed characterization of structure spaces and underlying energy landscapes is desirable but continues to challenge methods based on Molecular Dynamics. In this paper we propose a novel algorithm, SIfTER, which i...

There are synergistic effects of A? and tau protein in Alzheimer?s disease. A?1?42 protofibril seeds induce conversion of human tau protein into ?-sheet-rich toxic tau oligomers. However, the molecular mechanisms underlying such a conformational conversion are unclear. Here, we use extensive all atom replica exchange molecular dynamics simulations...

Mammalian target of rapamycin (mTOR) complexes play a pivotal role in the cell. Raptor and Rictor proteins interact with mTOR to form two distinct complexes, mTORC1 and mTORC2, respectively. While the domain structure of Raptor is known, current bioinformatics tools failed to classify the domains in Rictor. Here we focus on identifying specific dom...

Non-fibrillar neurotoxic amyloid (Aβ) oligomer structures are typically rich in β-sheets, which could be promoted by metal ions like Zn(2+). Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Aβ40 peptide conformations and Zn(2+) binding modes to probe the effects of secondary structure on Aβ dimerization en...

Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibri...

Ras is a small GTPase that acts as a molecular switch and is involved in multiple cellular signaling pathways. The catalytic domains of the three major isoforms, H‐, K‐, and N‐Ras share an identical effector lobe, and 90% sequence identity in their allosteric lobe. Ras isoforms have been shown experimentally to exhibit functional specificity yet th...

The Ras/Raf/MEK/ERK signal transduction pathway is a major regulator of cell proliferation activated by Ras-guanosine triphosphate (GTP). The oncogenic mutant RasQ61L is not able to hydrolyze GTP in the presence of Raf and thus is a constitutive activator of this mitogenic pathway. The Ras/Raf interaction is essential for the activation of the Raf...

Neuronal calcium sensor-1 (NCS-1) protein has a variety of different neuronal function and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). The substitution of argnine to glutamine at position 102 of NCS-1 protein was demonstrated to be associated with autism disease. However, there are two c...

Amyloid β protein is associated with the pathology of Alzheimer's disease. Metal ions can regulate the self-assembly pathway of amyloid peptides, leading to polymorphic non-fibrillar oligomers that are more neurotoxic than mature fibrils. It is still challenging to investigate the interactions between them at a molecular level by various experiment...

Hydrogels are proving to be an excellent class of materials for biomedical applications. The molecular self-assembly of designed MAX1 beta-hairpin peptides into fibrillar networks has emerged as a novel route to form responsive hydrogels. Herein, computational modeling techniques are used to investigate the relative arrangements of individual hairp...

EphB2 interacts with cell surface-bound ephrin ligands to relay bidirectional signals. Overexpression of the EphB2 receptor protein has been linked to different types of cancer. The SNEW (SNEWIQPRLPQH) peptide binds with high selectivity and moderate affinity to EphB2, inhibiting Eph–ephrin interactions by competing with ephrin ligands for the EphB...

Neuronal calcium sensor 1 (NCS-1) protein has a variety of different neuronal function and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). A single R102Q mutation in human NCS-1 protein was demonstrated to be associated with autism disease. Solution NMR study reported that this R102Q mutant...

Eph-ephrin interactions control the signal transduction between cells and play an important role in carcinogenesis and other diseases. The interactions between Eph receptors and ephrins of the same subclass are promiscuous; there are cross-interactions between some subclasses, but not all. To understand how Eph-ephrin interactions can be both promi...

Group VIII metal nanoparticles with variant morphologies were synthesized under carbon monoxide atmosphere. The important roles of CO in determining the surface formation of growing particles were studied by both experiments and density functional theory calculations, which suggest different growth mechanisms for these metals.

Tau is an intrinsically disordered protein (IDP) implicated in Alzheimer's disease. Recently, tau proteins were discovered to be able to catalyze self-acetylation, which may promote its pathological aggregation. Understanding the paradox of tau's random-like conformations, aggregation propensity, and enzymatic activity are challenging questions. We...

p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site a...

Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer's disease and other neurodegenerative disorders. Self-assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron-electron resona...

Experiments suggested that the fibrillation of the 11-25 fragment (hIAPP(11-25)) of human islet amyloid polypeptide (hIAPP or amylin) involves the formation of transient α-helical intermediates, followed by conversion to β-sheet-rich structure. However, atomic details of α-helical intermediates and the transition mechanism are mostly unknown. We in...

The fact that we observe a single conformational selection event during binding does not necessarily mean that only a single conformational selection event takes place, even though this is the common assumption. Here we suggest that conformational selection takes place not once in a given binding/allosteric event, but at every step along the allost...

The cellular network is highly interconnected. Pathways merge and diverge. They proceed through shared proteins and may change directions. How are cellular pathways controlled and their directions decided, coded, and read? These questions become particularly acute when we consider that a small number of pathways, such as signaling pathways that reg...