85 research outputs found
Geometric and Statistical Properties of the Mean-Field HP Model, the LS Model and Real Protein Sequences
Lattice models, for their coarse-grained nature, are best suited for the
study of the ``designability problem'', the phenomenon in which most of the
about 16,000 proteins of known structure have their native conformations
concentrated in a relatively small number of about 500 topological classes of
conformations. Here it is shown that on a lattice the most highly designable
simulated protein structures are those that have the largest number of
surface-core switchbacks. A combination of physical, mathematical and
biological reasons that causes the phenomenon is given. By comparing the most
foldable model peptides with protein sequences in the Protein Data Bank, it is
shown that whereas different models may yield similar designabilities,
predicted foldable peptides will simulate natural proteins only when the model
incorporates the correct physics and biology, in this case if the main folding
force arises from the differing hydrophobicity of the residues, but does not
originate, say, from the steric hindrance effect caused by the differing sizes
of the residues.Comment: 12 pages, 10 figure
Mean-Field HP Model, Designability and Alpha-Helices in Protein Structures
Analysis of the geometric properties of a mean-field HP model on a square
lattice for protein structure shows that structures with large number of switch
backs between surface and core sites are chosen favorably by peptides as unique
ground states. Global comparison of model (binary) peptide sequences with
concatenated (binary) protein sequences listed in the Protein Data Bank and the
Dali Domain Dictionary indicates that the highest correlation occurs between
model peptides choosing the favored structures and those portions of protein
sequences containing alpha-helices.Comment: 4 pages, 2 figure
Identification of ubiquitin/ubiquitin-like protein modification from tandem mass spectra with various PTMs
Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials
Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus
Diet and Energy-Sensing Inputs Affect TorC1-Mediated Axon Misrouting but Not TorC2-Directed Synapse Growth in a Drosophila Model of Tuberous Sclerosis
The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system
Non-equilibrium statistical mechanics: From a paradigmatic model to biological transport
Unlike equilibrium statistical mechanics, with its well-established
foundations, a similar widely-accepted framework for non-equilibrium
statistical mechanics (NESM) remains elusive. Here, we review some of the many
recent activities on NESM, focusing on some of the fundamental issues and
general aspects. Using the language of stochastic Markov processes, we
emphasize general properties of the evolution of configurational probabilities,
as described by master equations. Of particular interest are systems in which
the dynamics violate detailed balance, since such systems serve to model a wide
variety of phenomena in nature. We next review two distinct approaches for
investigating such problems. One approach focuses on models sufficiently simple
to allow us to find exact, analytic, non-trivial results. We provide detailed
mathematical analyses of a one-dimensional continuous-time lattice gas, the
totally asymmetric exclusion process (TASEP). It is regarded as a paradigmatic
model for NESM, much like the role the Ising model played for equilibrium
statistical mechanics. It is also the starting point for the second approach,
which attempts to include more realistic ingredients in order to be more
applicable to systems in nature. Restricting ourselves to the area of
biophysics and cellular biology, we review a number of models that are relevant
for transport phenomena. Successes and limitations of these simple models are
also highlighted.Comment: 72 pages, 18 figures, Accepted to: Reports on Progress in Physic
Multi-terminal transport measurements of MoS2 using a van der Waals heterostructure device platform
Cooperative Transport in a Potassium Ion Channel
Our current understanding of ion permeation through the selectivity filter of the KcsA potassium channel is based on the concept of a multi-ion transport mechanism. The details of this concerted movement, however, are not well understood. In the present paper we report on molecular dynamics simulations which provides new insights. It is shown that ion translocation is based on the collective hopping of ions and water molecules which is mediated by the flexible charged carbonyl groups lining the backbone of the pore. In particular, there is strong evidence for pairwise translocations where one ion and one water molecule form a bound state. We suggest a physical explanation of the observed phenomena employing a simple lattice model. It is argued that the water molecules can act as rectifiers during the hopping of ion-water pairs
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