Biomedical subjects

Feng Ding

Publications and source records attributed to Feng Ding.

At least 19 recordsLinked to original sources

PubMed2026

A machine learning-derived intratumoral heterogeneity-related signature predicts the prognosis for and therapeutic response in patients with skin cutaneous melanoma.

BACKGROUND: Reliable biomarkers for predicting prognosis and therapeutic response in skin cutaneous melanoma (SKCM) remain limited. This study aimed to develop an intratumoral heterogeneity (ITH)-related prognostic signature for SKCM using integrative machine learning. METHODS: RNA sequencing (RNA-seq) data from 472 SKCM patients in The Cancer Genome Atlas (TCGA) and 214 patients in the GSE65904 cohort were analyzed. ITH scores were calculated using the DEPTH2 algorithm. Differentially expressed genes (DEGs) were identified between high- and low-ITH groups [|log2fold change (FC)| ≥1, false discovery rate (FDR) <0.05]. Based on 38 prognostic DEGs identified by univariate Cox regression, we employed an integrative framework of 101 machine learning algorithm combinations to construct prognostic models in the TCGA training cohort. The model with the highest average concordance index (C-index) was validated in the GSE65904 cohort and selected as the prognostic ITH-related signature (PIRS). Associations of the PIRS risk score with tumor mutational burden (TMB), immune cell infiltration, immune checkpoint gene expression, and drug sensitivity were systematically evaluated. Model performance was assessed using receiver operating characteristic (ROC) curves and Cox regression analyses. RESULTS: A 38-gene PIRS was constructed using the plsRcox algorithm. Patients with high PIRS risk scores exhibited significantly poorer overall survival (OS) in both the TCGA and Gene Expression Omnibus (GEO) cohorts. The PIRS was identified as an independent prognostic factor, with area under the curve (AUC) values of 0.779, 0.734, and 0.756 for 1-, 3-, and 5-year survival, respectively. High-risk samples displayed significantly lower TMB (P<0.05), reduced immune and stromal cell infiltration (P<0.001), downregulated immune function, and decreased expression of immune checkpoint genes. Additionally, high- and low-PIRS risk score groups exhibited distinct sensitivity patterns to different classes of targeted agents. CONCLUSIONS: The machine learning-derived PIRS robustly predicts prognosis in SKCM patients. Its clinical application is promising for optimizing patient risk stratification and treatment decisions, though further prospective validation is warranted.

Skin cutaneous melanoma (SKCM)↗

PubMed2025

Integration of multiple omics reveals key targets and cellular mechanisms for intervention in sarcopenia.

BACKGROUND: Sarcopenia, an age-related syndrome characterized by progressive loss of muscle mass, strength, and function, presents a significant global health burden with limited therapeutic interventions. This study integrates genomic causality, multi-tissue omics, and cellular mediation analyses to identify and prioritize mechanistically grounded therapeutic targets. METHODS: A multi-tiered analytical framework was applied, beginning with two-sample Mendelian randomization (MR) to infer causal relationships between 4907 plasma proteins (cis-pQTLs from 35,559 individuals) and sarcopenia traits in Pan-UK Biobank participants. Bayesian colocalization and transcriptomic validation in human sarcopenia muscle biopsies were employed to prioritize targets. Cellular mediation analysis quantified contributions of immune and stromal cell subtypes to protein-trait pathways using transcriptomic deconvolution. RESULTS: MR identified 1237 plasma proteins causally associated with sarcopenia traits, with six targets (HGFAC, GATM, HMOX2, F2, LMAN2L, HPGDS) validated through colocalization, transcriptomic expression, and sarcopenia-related dysregulation. Cellular mediation revealed immune mechanisms underlying HGFAC's effects, with CD4+ regulatory T cells mediating 3.49 % of its impact on sarcopenia traits. Prothrombin exhibited muscle-protective effects independent of coagulation. CONCLUSION: This study establishes a causal map linking plasma proteins to sarcopenia through immune-stromal interactions. The integration of MR, multi-omics validation, and cellular mediation prioritizes six proteins as actionable targets, supporting repurposing of thrombin inhibitors and development of immunometabolic therapies. The framework bridges genomic causality with cellular pathophysiology, advancing precision strategies for age-related muscle decline.

Humans↗

PubMed2025

Polyploidy-mediated variations in glutamate receptor proteins linked to Fusarium wilt resistance in upland cotton.

Cotton production in the US faces a serious threat from Fusarium oxysporum f. sp. vasinfectum race 4 (FOV4), a soil-borne fungus causing Fusarium wilt by infecting the roots and vascular system of susceptible cotton, leading to rapid wilting and death. Here, we investigate genetic mechanisms of resistance to FOV4 in the highly resistant upland cotton genotype "U1" using an early-generation segregating biparental population ("U1" × "CSX8308") with comprehensive genomic resources. Reference-grade genomic assemblies of the parents revealed minor structural variations between "U1" haplotypes, a high degree of collinearity at chromosome synteny and micro-synteny levels, and significant divergence from "CSX8308" with 8.9 million SNPs. QTL analysis identified significant markers on chromosomes D03 and A02 linked to reduced Fusarium wilt severity. Within these regions, two glutamate-receptor-like (GLR) genes showed structural variation and overlapped between translocated segments on A02 and D03, suggesting a rare but important reinforcing effect of parallel evolution between susceptible and resistant genotypes. Transcriptome profiles of "U1" under FOV4 infection reveal activation of calcium-binding proteins and transcription factors regulating plant hormones (ethylene, abscisic acid, jasmonic acid, and salicylic acid), along with enzymes involved in cell wall remodeling and phytoalexin production. Advancing cotton improvement depends on incorporating durable genetic disease resistance into high-yielding, high-quality cultivars.

Fusarium↗

PubMed2006

Multiscale modeling of nucleosome dynamics.

Nucleosomes form the fundamental building blocks of chromatin. Subtle modifications of the constituent histone tails mediate chromatin stability and regulate gene expression. For this reason, it is important to understand structural dynamics of nucleosomes at atomic levels. We report a novel multiscale model of the fundamental chromatin unit, a nucleosome, using a simplified model for rapid discrete molecular dynamics simulations and an all-atom model for detailed structural investigation. Using a simplified structural model, we perform equilibrium simulations of a single nucleosome at various temperatures. We further reconstruct all-atom nucleosome structures from simulation trajectories. We find that histone tails bind to nucleosomal DNA via strong salt-bridge interactions over a wide range of temperatures, suggesting a mechanism of chromatin structural organization whereby histone tails regulate inter- and intranucleosomal assemblies via binding with nucleosomal DNA. We identify specific regions of the histone core H2A/H2B-H4/H3-H3/H4-H2B/H2A, termed "cold sites", which retain a significant fraction of contacts with adjoining residues throughout the simulation, indicating their functional role in nucleosome organization. Cold sites are clustered around H3-H3, H2A-H4 and H4-H2A interhistone interfaces, indicating the necessity of these contacts for nucleosome stability. Essential dynamics analysis of simulation trajectories shows that bending across the H3-H3 is a prominent mode of intranucleosomal dynamics. We postulate that effects of salts on mononucleosomes can be modeled in discrete molecular dynamics by modulating histone-DNA interaction potentials. Local fluctuations in nucleosomal DNA vary significantly along the DNA sequence, suggesting that only a fraction of histone-DNA contacts make strong interactions dominating mononucleosomal dynamics. Our findings suggest that histone tails have a direct functional role in stabilizing higher-order chromatin structure, mediated by salt-bridge interactions with adjacent DNA.

Chromatin↗

PubMed2006

A structural model reveals energy transduction in dynein.

Intracellular active transport is driven by ATP-hydrolyzing motor proteins that move along cytoskeletal filaments. In particular, the microtubule-associated dynein motor is involved in the transport of organelles and vesicles, the maintenance of the Golgi, and mitosis. However, unlike kinesin and myosin, the mechanism by which dynein converts chemical energy into mechanical force remains largely a mystery, due primarily to the lack of a high-resolution molecular structure. Using homology modeling and normal mode analysis, we propose a complete atomic structure and a mechanism for force generation by the motor protein dynein. In agreement with very recent electron microscopy (EM) reconstructions showing dynein as a ring-shaped heptamer, our model consists of six ATPases of the AAA (ATPases associated with various cellular activities) superfamily and a C-terminal domain, which is experimentally known to control motor function. Our model shows a coiled coil spanning the diameter of the motor that accounts for previously unidentified structures in EM studies and provides a potential mechanism for long-range communication between the AAA domains. Furthermore, normal mode analysis reveals that the subunits of the motor that contain the nucleotide binding sites exhibit minimal movement, whereas the rest of the motor is very mobile. Our analysis suggests the likely domain rearrangements of the motor unit that generate its power stroke. This study provides insights into the structure and function of dynein that can guide further experimental investigations into energy transduction in dynein.

Amino Acid Sequence↗

PubMed2006

Passively correcting phase drift in two-dimensional infrared spectroscopy.

Heterodyned two-dimensional (2D) IR spectra often suffer from inaccurate pulse delays and phase drift. We report a passive method of correcting these two inaccuracies by using wedged optics for subfemtosecond pulse delay resolution and reference measurements for phase corrections. Our approach is easy to implement into existing 2D IR spectrometers and makes experiments requiring long-term phase stability possible, such as the collection of 3D IR spectra.

Journal Article↗

PubMed2006

iFold: a platform for interactive folding simulations of proteins.

UNLABELLED: We built a novel web-based platform for performing discrete molecular dynamics simulations of proteins. In silico protein folding involves searching for minimal frustration in the vast conformational landscape. Conventional approaches for simulating protein folding insufficiently address the problem of simulations in relevant time and length scales necessary for a mechanistic understanding of underlying biomolecular phenomena. Discrete molecular dynamics (DMD) offers an opportunity to bridge the size and timescale gaps and uncover the structural and biological properties of experimentally undetectable protein dynamics. The iFold server supports large-scale simulations of protein folding, thermal denaturation, thermodynamic scan, simulated annealing and p(fold) analysis using DMD and coarse-grained protein model with structure-based Gō-interactions between amino acids. AVAILABILITY: http://ifold.dokhlab.org

Amino Acid Sequence↗

PubMed2006

Emergence of protein fold families through rational design.

Diverse proteins with similar structures are grouped into families of homologs and analogs, if their sequence similarity is higher or lower, respectively, than 20%-30%. It was suggested that protein homologs and analogs originate from a common ancestor and diverge in their distinct evolutionary time scales, emerging as a consequence of the physical properties of the protein sequence space. Although a number of studies have determined key signatures of protein family organization, the sequence-structure factors that differentiate the two evolution-related protein families remain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologous families, lead to distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs. We propose that such differentiation results in the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa, to computationally design protein sequences that correspond to the same fold family. We find that analogous proteins emerge when a backbone structure deviates only 1-2 angstroms root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to approximately 25%-30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences, thereby validating our computational design methodology.

Computational Biology↗

PubMed2006

Graphitic encapsulation of catalyst particles in carbon nanotube production.

A new model is proposed for the encapsulation of catalyst metal particles by graphite layers that are obtained, for example, in low-temperature chemical vapor deposition production of carbon nanotubes (CNTs). In this model graphite layers are primarily formed from the dissolved carbon atoms in the metal-carbide particle when the particle cools. This mechanism is in good agreement with molecular dynamics simulations (which show that precipitated carbon atoms preferentially form graphite sheets instead of CNTs at low temperatures) and experimental results (e.g., encapsulated metal particles are found in low-temperature zones and CNTs in high-temperature regions of production apparatus, very small catalyst particles are generally not encapsulated, and the ratio of the number of graphitic layers to the diameter of the catalyst particle is typically 0.25 nm(-1)).

Journal Article↗

PubMed2006

Fast complementation of split fluorescent protein triggered by DNA hybridization.

Fluorescent proteins have proven to be excellent reporters and biochemical sensors with a wide range of applications. In a split form, they are not fluorescent, but their fluorescence can be restored by supplementary protein-protein or protein-nucleic acid interactions that reassemble the split polypeptides. However, in prior studies, it took hours to restore the fluorescence of a split fluorescent protein because the formation of the protein chromophore slowly occurred de novo concurrently with reassembly. Here we provide evidence that a fluorogenic chromophore can self-catalytically form within an isolated N-terminal fragment of the enhanced green fluorescent protein (EGFP). We show that restoration of the split protein fluorescence can be driven by nucleic acid complementary interactions. In our assay, fluorescence development is fast (within a few minutes) when complementary oligonucleotide-linked fragments of the split EGFP are combined. The ability of our EGFP system to respond quickly to DNA hybridization should be useful for detecting the kinetics of many other types of pairwise interactions both in vitro and in living cells.

DNA↗

PubMed2006

Topological determinants of protein domain swapping.

Protein domain swapping has been repeatedly observed in a variety of proteins and is believed to result from destabilization due to mutations or changes in environment. Based on results from our studies and others, we propose that structures of the domain-swapped proteins are mainly determined by their native topologies. We performed molecular dynamics simulations of seven different proteins, known to undergo domain swapping experimentally, under mildly denaturing conditions and found in all cases that the domain-swapped structures can be recapitulated by using protein topology in a simple protein model. Our studies further indicated that, in many cases, domain swapping occurs at positions around which the protein tends to unfold prior to complete unfolding. This, in turn, enabled prediction of protein structural elements that are responsible for domain swapping. In particular, two distinct domain-swapped dimer conformations of the focal adhesion targeting domain of focal adhesion kinase were predicted computationally and were supported experimentally by data obtained from NMR analyses.

Animals↗

PubMed2006

Atomistic simulations of catalyzed carbon nanotube growth.

We review the advances made in understanding the mechanism of catalyzed carbon nanotube growth, with the main focus on direct dynamics and molecular dynamics studies of single-walled carbon nanotube (SWNT) growth. These studies have deepened our understanding of the catalytic SWNT nucleation and growth mechanisms, but more accurate and efficient methods are required for a complete investigation at experimental growth conditions.

Catalysis↗

PubMed2005

Direct observation of protein folding, aggregation, and a prion-like conformational conversion.

Protein conformational transition from alpha-helices to beta-sheets precedes aggregation of proteins implicated in many diseases, including Alzheimer and prion diseases. Direct characterization of such transitions is often hindered by the complicated nature of the interaction network among amino acids. A recently engineered small protein-like peptide with a simple amino acid composition features a temperature-driven alpha-helix to beta-sheet conformational change. Here we studied the conformational transition of this peptide by molecular dynamics simulations. We observed a critical temperature, below which the peptide folds into an alpha-helical coiled-coil state and above which the peptide misfolds into beta-rich structures with a high propensity to aggregate. The structures adopted by this peptide during low temperature simulations have a backbone root mean square deviation less than 2 A from the crystal structure. At high temperatures, this peptide adopts an amyloid-like structure, which is mainly composed of coiled anti-parallel beta-sheets with the cross-beta-signature of amyloid fibrils. Most strikingly, we observed conformational conversions in which an alpha-helix is converted into a beta-strand by proximate stable beta-sheets with exposed hydrophobic surfaces and unsaturated hydrogen bonds. Our study suggested a possible generic molecular mechanism of the template-mediated aggregation process, originally proposed by Prusiner (Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13363-13383) to account for prion infectivity.

Amyloid↗

PubMed2005

Heterodyned fifth-order two-dimensional IR spectroscopy: third-quantum states and polarization selectivity.

A heterodyned fifth-order two-dimensional (2D) IR spectrum of a model coupled oscillator system, Ir(CO)(2)(C(5)H(7)O(2)), is reported. The spectrum is generated by a pulse sequence that probes the eigenstate energies up to the second overtone and combination bands, providing a more rigorous potential-energy surface of the coupled carbonyl local modes than can be obtained with third-order spectroscopy. Furthermore, the pulse sequence is designed to generate and then rephase a two-quantum coherence so that the spectrum is line narrowed and the resolution improved for inhomogeneously broadened systems. Features arising from coherence transfer processes are identified, which are more pronounced than in third-order 2D IR spectroscopy because the transition dipoles of the second overtone and combination states are not rigorously orthogonal, relaxing the polarization constraints on the signal intensity for these features. The spectrum provides a stringent test of cascading signals caused by third-order emitted fields and no cascading is observed. In the Appendix, formulas for calculating the signal intensities for resonant fifth-order spectroscopies with arbitrarily polarized pulses and transition dipoles are reported. These relationships are useful for interpreting and designing polarization conditions to enhance specific spectral features.

Journal Article↗

PubMed2005

Molecular origin of polyglutamine aggregation in neurodegenerative diseases.

Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35-40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel beta-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the beta-helices observed in simulations, all residues adopt beta-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 +/- 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel beta-hairpins in their ground state, in agreement with experiments. The lower stability of mutant beta-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation.

Journal Article↗

PubMed2005

Reconstruction of the src-SH3 protein domain transition state ensemble using multiscale molecular dynamics simulations.

We use an integrated computational approach to reconstruct accurately the transition state ensemble (TSE) for folding of the src-SH3 protein domain. We first identify putative TSE conformations from free energy surfaces generated by importance sampling molecular dynamics for a fully atomic, solvated model of the src-SH3 protein domain. These putative TSE conformations are then subjected to a folding analysis using a coarse-grained representation of the protein and rapid discrete molecular dynamics simulations. Those conformations that fold to the native conformation with a probability (P(fold)) of approximately 0.5, constitute the true transition state. Approximately 20% of the putative TSE structures were found to have a P(fold) near 0.5, indicating that, although correct TSE conformations are populated at the free energy barrier, there is a critical need to refine this ensemble. Our simulations indicate that the true TSE conformations are compact, with a well-defined central beta sheet, in good agreement with previous experimental and theoretical studies. A structured central beta sheet was found to be present in a number of pre-TSE conformations, however, indicating that this element, although required in the transition state, does not define it uniquely. An additional tight cluster of contacts between highly conserved residues belonging to the diverging turn and second beta-sheet of the protein emerged as being critical elements of the folding nucleus. A number of commonly used order parameters to identify the transition state for folding were investigated, with the number of native Cbeta contacts displaying the most satisfactory correlation with P(fold) values.

Models, Molecular↗

PubMed2005

Vibrational dynamics of ions in glass from fifth-order two-dimensional infrared spectroscopy.

The vibrational dynamics of the first four antisymmetric stretch vibrational levels of azide in an ionic glass have been measured and correlated using a heterodyned fifth-order two-dimensional infrared pulse sequence. By rephasing a two-quantum coherence, a process not possible with third-order spectroscopy, solvent effects on the frequencies and anharmonicities of the potential energy surface are measured. Fifth-order pulse sequences are another step towards precisely controlling vibrational coherence in analogy to the manipulation of spins in NMR but with ultrafast time resolution.

Journal Article↗

PubMed2005

Heterodyned fifth-order 2D-IR spectroscopy of the azide ion in an ionic glass.

A heterodyned fifth-order infrared pulse sequence has been used to measure a two-dimensional infrared (2D-IR) spectrum of azide in the ionic glass 3KNO3:2Ca(NO3)2. By rephasing a two-quantum coherence, a process not possible with third-order spectroscopy, the 2D-IR spectra are line narrowed, allowing the frequencies, anharmonicities, and their correlations to be measured for the first four (nu=0-3) antisymmetric stretch vibrational levels. In this glass, the vibrational levels are extremely inhomogeneously broadened. Furthermore, the glass shifts the energy of the nu=3 state more than the others, causing an inhomogeneous distribution in the anharmonic constants that are partially correlated to the inhomogeneous distribution of the fundamental frequency. These effects are discussed in light of the strong interactions that exist between the charged solute and solvent. Since this is the first example of a heterodyned fifth-order infrared pulse sequence, possible cascaded contributions to the signal are investigated. No evidence of cascaded signals is found. Compared to third-order spectroscopies, fifth-order pulse sequences provide advanced control over vibrational coherence and population times that promise to extend the capabilities of ultrafast infrared spectroscopy.

Journal Article↗