Eng Hui Yap - Academia.edu (original) (raw)

Papers by Eng Hui Yap

Structure

Highlights d Structure-based method (ProtLID) is developed to find ligands in a subproteome d Pro... more Highlights d Structure-based method (ProtLID) is developed to find ligands in a subproteome d ProtLID designs residue-specific pharmacophores derived from molecular dynamics d The residue-based pharmacophores are matched to candidate ligand structures d ProtLID is used to explore receptor-ligand interactions in the immunological synapse

Proceedings of the National Academy of Sciences of the United States of America, Oct 4, 2016

There are seven β-tubulin isotypes present in distinct quantities in mammalian cells of different... more There are seven β-tubulin isotypes present in distinct quantities in mammalian cells of different origin. Altered expression of β-tubulin isotypes has been reported in cancer cell lines resistant to microtubule stabilizing agents (MSAs) and in human tumors resistant to Taxol. To study the relative binding affinities of MSAs, tubulin from different sources, with distinct β-tubulin isotype content, were specifically photolabeled with a tritium-labeled Taxol analog, 2-(m-azidobenzoyl)taxol, alone or in the presence of MSAs. The inhibitory effects elicited by these MSAs on photolabeling were distinct for β-tubulin from different sources. To determine the exact amount of drug that binds to different β-tubulin isotypes, bovine brain tubulin was photolabeled and the isotypes resolved by high-resolution isoelectrofocusing. All bands were analyzed by mass spectrometry following cyanogen bromide digestion, and the identity and relative quantity of each β-tubulin isotype determined. It was fou...

Journal of computational chemistry, Jan 2, 2016

We present the open source distributed software package Poisson-Boltzmann Analytical Method (PB-A... more We present the open source distributed software package Poisson-Boltzmann Analytical Method (PB-AM), a fully analytical solution to the linearized PB equation, for molecules represented as non-overlapping spherical cavities. The PB-AM software package includes the generation of outputs files appropriate for visualization using visual molecular dynamics, a Brownian dynamics scheme that uses periodic boundary conditions to simulate dynamics, the ability to specify docking criteria, and offers two different kinetics schemes to evaluate biomolecular association rate constants. Given that PB-AM defines mutual polarization completely and accurately, it can be refactored as a many-body expansion to explore 2- and 3-body polarization. Additionally, the software has been integrated into the Adaptive Poisson-Boltzmann Solver (APBS) software package to make it more accessible to a larger group of scientists, educators, and students that are more familiar with the APBS framework. © 2016 Wiley P...

Glia, 2016

Nuc-ErbB3 an alternative transcript from the ErbB3 locus binds to a specific DNA motif and associ... more Nuc-ErbB3 an alternative transcript from the ErbB3 locus binds to a specific DNA motif and associates with Schwann cell chromatin. Here we generated a nuc-ErbB3 knockin mouse that lacks nuc-ErbB3 expression in the nucleus without affecting the neuregulin-ErbB3 receptor signaling. Nuc-ErbB3 knockin mice exhibit hypermyelination and aberrant myelination at the paranodal region. This phenotype is attributed to de-repression of myelination associated gene transcription following loss of nuc-ErbB3 and histone H3K27me3 promoter occupancy. Nuc-ErbB3 knockin mice exhibit reduced association of H3K27me3 with myelination-associated gene promoters and increased RNA Pol-II rate of transcription of these genes. In addition, nuc-ErbB3 directly regulates levels of H3K27me3 in Schwann cells. Nuc-ErbB3 knockin mice exhibit significant decrease of histone H3K27me3 methyltransferase (HMT) activity and reduced levels of H3K27me3. Collectively, nuc-ErbB3 is a master transcriptional repressor, which regu...

Annual Review of Physical Chemistry, 2014

Computational modeling at the atomistic and mesoscopic levels has undergone dramatic development ... more Computational modeling at the atomistic and mesoscopic levels has undergone dramatic development in the last 10 years in order to meet the challenge of adequately accounting for the many-body nature of intermolecular interactions. At the heart of this challenge is the ability to identify the strengths and specific limitations of pairwise-additive interactions, and improving classical models to explicitly account for many-body effects, and consequently enhance their ability to describe a wider range of reference data and to build confidence in their predictive capacity. However the corresponding computational cost of these advanced classical models increases significantly enough so that statistical convergence of condensed phase observables becomes more difficult to achieve. Here we review a hierarchy of potential energy surface models used in molecular simulations for systems with many degrees of freedom that best meet the trade off between accuracy and computational speed in order to define a "sweet spot" for a given scientific problem of interest.

Proteins: Structure, Function, and Bioinformatics, 2007

We develop a sequence based carbon model to incorporate a mean field estimate of the orientatio... more We develop a sequence based carbon model to incorporate a mean field estimate of the orientation dependence of the polypeptide chain that give rise to specific hydrogen bond pairing to stabilize helices and sheets. We illustrate the success of the new protein model to improve on thermodynamic measures and folding mechanism of proteins L and G. Compared to our previous 3flavor model without hydrogen bond, the new model shows greater folding cooperativity and improvements in designability of protein sequences, as well as predicting correct trends for kinetic rates and mechanism for proteins L and G.

Journal of Molecular Biology, 2014

Secreted and cell-surface-localized members of the immunoglobulin superfamily (IgSF) play central... more Secreted and cell-surface-localized members of the immunoglobulin superfamily (IgSF) play central roles in regulating adaptive and innate immune responses and are prime targets for the development of protein-based therapeutics. An essential activity of the ectodomains of these proteins is the specific recognition of cognate ligands, which are often other members of the IgSF. In this work, we provide functional insight for this important class of proteins through the development of a clustering algorithm that groups together extracellular domains of the IgSF with similar binding preferences. Information from hidden Markov model-based sequence profiles and domain architecture is calibrated against manually curated protein interaction data to define functional families of IgSF proteins. The method is able to assign 82% of the 477 extracellular IgSF protein to a functional family, while the rest are either single proteins with unique function or proteins that could not be assigned with the current technology. The functional clustering of IgSF proteins generates hypotheses regarding the identification of new cognate receptor-ligand pairs and reduces the pool of possible interacting partners to a manageable level for experimental validation.

Journal of Molecular Biology, 2007

We use a coarse-grained protein model to characterize the critical nucleus, structural stability,... more We use a coarse-grained protein model to characterize the critical nucleus, structural stability, and fibril elongation propensity of Aβ 1−40 oligomers for the C 2x and C 2z quaternary forms proposed by solid-state NMR. By estimating equilibrium populations of structurally stable and unstable protofibrils, we determine the shift in the dominant population from free monomer to ordered fibril at a critical nucleus of ten chains for the C 2x and C 2z forms. We find that a minimum assembly of 16 monomer chains is necessary to mimic a mature fibril, and show that its structural stability correlates with a plateau in the hydrophobic residue density and a decrease in the likelihood of losing hydrophobic interactions by rotating the fibril subunits. While Aβ 1−40 protofibrils show similar structural stability for both C 2x and C 2z quaternary structures, we find that the fibril elongation propensity is greater for the C 2z form relative to the C 2x form. We attribute the increased propensity for elongation of the C 2z form as being due to a stagger in the interdigitation of the N-terminal and C-terminal β-strands, resulting in structural asymmetry in the presented fibril ends that decreases the amount of incorrect addition to the N terminus on one end. We show that because different combinations of stagger and quaternary structure affect the structural symmetry of the fibril end, we propose that differences in quaternary structures will affect directional growth patterns and possibly different morphologies in the mature fiber.

Journal of Chemical Theory and Computation, 2010

We derive a new numerical approach to solving the linearized Poisson Boltzmann equation (PBE) by ... more We derive a new numerical approach to solving the linearized Poisson Boltzmann equation (PBE) by representing the protein surface as a collection of spheres in which the surface charges can then be iteratively solved by new analytical multipole methods previously introduced by us [Lotan & Head-Gordon, 2006]. We show that our Poisson Boltzmann semi-analytical method, PB-SAM, realizes better accuracy, more flexible memory management, and at reduced cost relative to either finite difference or boundary element method PBE solvers. We provide two new benchmarks of PBE solution accuracy to test the numerical PBE solutions based on (1) arrays of up to hundreds of spherical low dielectric geometries with asymmetric charges in which mutual polarization is treated exactly, and (2) two overlapping spheres with increasing charge asymmetry by solving the PB-SAM method to very high pole order. We illustrate the strength of the PB-SAM approach by computing the potential profile of an array of 60 T1-particle forming monomers of the bromine mosaic virus.

Journal of Chemical Theory and Computation, 2013

We have recently introduced a method termed Poisson-Boltzmann semi-analytical method (PB-SAM) for... more We have recently introduced a method termed Poisson-Boltzmann semi-analytical method (PB-SAM) for solving the linearized Poisson-Boltzmann equation for large numbers of arbitrarily shaped dielectric cavities with controlled precision. In this work we extend the applicability of the PB-SAM approach by deriving force and torque expressions that fully account for mutual polarization in both the zero and first order derivative of the surface charges, that can now be embedded into a Brownian dynamics scheme to look at electrostatic-driven mesoscale assembly and kinetics. We demonstrate the capabilities of the PB-SAM approach by simulating the protein concentration effects on the biomolecular rate of association of barnase and barstar, under periodic boundary conditions and evaluated through mean first passage times. We apply PB-SAM to the pseudo-first order reaction rate conditions in which either barnase or barstar are in great excess relative to the other protein (124:1). This can be considered a specific case in which the PB-SAM approach can be applied to crowding conditions in which crowders are not inert but can form interactions with other molecules.

Accounts of Chemical Research, 2008

Protein aggregation can be defined as the sacrifice of stabilizing intrachain contacts of the fol... more Protein aggregation can be defined as the sacrifice of stabilizing intrachain contacts of the folded state that are replaced with interchain contacts to form aggregate structures. The resulting aggregate morphologies range from amorphous structures without long-range order typical of non-disease proteins involved in inclusion bodies, to highly structured fibril assemblies typical of amyloid disease proteins. In this Account, we describe the development and application of computational models for the investigation of non-disease and disease protein aggregation as illustrated for the proteins L and G and the Alzheimer's A systems. In each case we validate the models against relevant experimental observables, and then expand on the experimental window to better elucidate the link between molecular properties and aggregation outcomes. Our studies show that each class of protein exhibits distinct aggregation mechanisms that are dependent on protein sequence, protein concentration, and solution conditions. Non-disease proteins can have native structural elements in the denatured state ensemble, or rapidly form early folding intermediates, which offers avenues of protection against aggregation even at relatively high concentrations. The possibility that early folding intermediates may be evolutionary selected for their protective role against unwanted aggregation could be a useful strategy for reengineering sequences to slow aggregation and increase folding yield in industrial protein production. The observed oligomeric aggregates we see for proteins L and G may represent the nuclei for larger aggregates, not just for large amorphous inclusion bodies, but potentially as the seeds of ordered fibrillar aggregates, since most non-disease proteins can form amyloid fibrils under conditions that destabilize the native state. By contrast, amyloidogenic protein sequences such as A 1-40,42 and the Familial Alzheimer's Disease (FAD) mutants favor aggregation into ordered fibrils once the free energy barrier for forming a critical nucleus is crossed. However, the structural characteristics and oligomer size of the soluble nucleation species have yet to be determined experimentally for any disease peptide sequence, and the molecular mechanism of polymerization that eventually delineates a mature fibril is unknown. This is in part due to the limited experimental access to very low peptide concentrations that are required to characterize these early aggregation events, providing an opportunity for theoretical studies to bridge the gap between the monomer and fibril endpoints and to develop testable hypotheses. Our model shows that A 1-40 requires as few as 6-10 monomer chains (depending on sequence), to begin manifesting the cross order that is a signature of formation of amyloid filaments and/or fibrils assessed in dye-binding kinetic assays. The richness of the oligomeric structures and viable filament and fibril polymorphs we observe may offer structural clues to disease virulence variations that are seen for the WT and hereditary mutants.