共查询到20条相似文献,搜索用时 15 毫秒
1.
Background
Many processes in molecular biology involve the recognition of short sequences of nucleic-or amino acids, such as the binding of immunogenic peptides to major histocompatibility complex (MHC) molecules. From experimental data, a model of the sequence specificity of these processes can be constructed, such as a sequence motif, a scoring matrix or an artificial neural network. The purpose of these models is two-fold. First, they can provide a summary of experimental results, allowing for a deeper understanding of the mechanisms involved in sequence recognition. Second, such models can be used to predict the experimental outcome for yet untested sequences. In the past we reported the development of a method to generate such models called the Stabilized Matrix Method (SMM). This method has been successfully applied to predicting peptide binding to MHC molecules, peptide transport by the transporter associated with antigen presentation (TAP) and proteasomal cleavage of protein sequences. 相似文献2.
Deep generative models have gained recent popularity for chemical design. Many of these models have historically operated in 2D space; however, more recently explicit 3D molecular generative models have become of interest, which are the topic of this article. Dozens of published models have been developed in the last few years to generate molecules directly in 3D, outputting both the atom types and coordinates, either in one-shot or adding atoms or fragments step-by-step. These 3D generative models can also be guided by structural information such as a binding pocket representation to successfully generate molecules with docking score ranges similar to known actives, but still showing lower computational efficiency and generation throughput than 1D/2D generative models and sometimes producing unrealistic conformations. We advocate for a unified benchmark of metrics to evaluate generation and propose perspectives to be addressed in next implementations. 相似文献
3.
Modulation of microtubule dynamics by drugs: a paradigm for the actions of cellular regulators 总被引:7,自引:0,他引:7
Microtubules are intrinsically dynamic polymers. Two kinds of dynamic behaviors, dynamic instability and treadmilling, are important for microtubule function in cells. Both dynamic behaviors appear to be tightly regulated, but the cellular molecules and the mechanisms responsible for the regulation remain largely unexplored. While microtubule dynamics can be modulated transiently by the interaction of regulatory molecules with soluble tubulin, the microtubule itself is likely to be the primary target of cellular molecules that regulate microtubule dynamics. The antimitotic drugs that modulate microtubule dynamics serve as excellent models for such cellular molecules. Our laboratory has been investigating the interactions of small drug molecules and stabilizing microtubule-associated proteins (MAPs) with microtubule surfaces and ends. We find that drugs such as colchicine, vinblastine, and taxol, and stabilizing MAPs such as tau, strongly modulate microtubule dynamics at extremely low concentrations under conditions in which the microtubule polymer mass is minimally affected. The powerful modulation of the dynamics is brought about by the binding of only a few drug or MAP molecules to distinct binding sites at the microtubule surface or end. Based upon our understanding of the well-studied drugs and stabilizing MAPs, it is clear that molecules that regulate dynamics such as Kin 1 and stathmin could bind to a large number of distinct tubulin sites on microtubules and employ an array of mechanisms to selectively and powerfully regulate microtubule dynamics and dynamics-dependent cellular functions. 相似文献
4.
Daniel Riveline 《Journal of nanobiotechnology》2013,11(Z1):S1
At scales below micrometers, Brownian motion dictates most of the behaviors. The simple observation of a colloid is striking: a permanent and random motion is seen, whereas inertial forces play a negligible role. This Physics, where velocity is proportional to force, has opened new horizons in biology. The random feature is challenged in living systems where some proteins - molecular motors - have a directed motion whereas their passive behaviors of colloid should lead to a Brownian motion. Individual proteins, polymers of living matter such as DNA, RNA, actin or microtubules, molecular motors, all these objects can be viewed as chains of colloids. They are submitted to shocks from molecules of the solvent. Shapes taken by these biopolymers or dynamics imposed by motors can be measured and modeled from single molecules to their collective effects. Thanks to the development of experimental methods such as optical tweezers, Atomic Force Microscope (AFM), micropipettes, and quantitative fluorescence (such as Förster Resonance Energy Transfer, FRET), it is possible to manipulate these individual biomolecules in an unprecedented manner: experiments allow to probe the validity of models; and a new Physics has thereby emerged with original biological insights. Theories based on statistical mechanics are needed to explain behaviors of these systems. When force-extension curves of these molecules are extracted, the curves need to be fitted with models that predict the deformation of free objects or submitted to a force. When velocity of motors is altered, a quantitative analysis is required to explain the motions of individual molecules under external forces. This lecture will give some elements of introduction to the lectures of the session 'Nanophysics for Molecular Biology'. 相似文献
5.
Xie P 《International journal of biological sciences》2010,6(7):665-674
Kinesin molecules are motor proteins capable of moving along microtubule by hydrolyzing ATP. They generally have several forms of construct. This review focuses on two of the most studied forms: monomers such as KIF1A (kinesin-3 family) and dimers such as conventional kinesin (kinesin-1 family), both of which can move processively towards the microtubule plus end. There now exist numerous models that try to explain how the kinesin molecules convert the chemical energy of ATP hydrolysis into the mechanical energy to "power" their processive movement along microtubule. Here, we attempt to present a comprehensive review of these models. We further propose a new hybrid model for the dimeric kinesin by combining the existing models and provide a framework for future studies in this subject. 相似文献
6.
We develop a probabilistic model for the binding of a small linear polymer to a larger chain. We assume that we can approximate the energy of interaction of the two chains by summing the pairwise interactions between subunits. Because the energy of interaction between a pair of subunits can depend on neighboring subunits, which we assume vary along the chain, we assign the pairwise energies of interactions according to a specified probability distribution. Thus we develop a statistical model for the binding of two molecules. While such models may not be appropriate for studying the interaction of a particular pair of molecules, they can provide insight into questions that deal with populations of molecules, such as why do MHC molecules bind peptides of a certain size? Here we analyze in detail the special case of a heterodimer binding to a polymer. 相似文献
7.
Diggle SP Gardner A West SA Griffin AS 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2007,362(1483):1241-1249
The term quorum sensing (QS) is used to describe the communication between bacterial cells, whereby a coordinated population response is controlled by diffusible molecules produced by individuals. QS has not only been described between cells of the same species (intraspecies), but also between species (interspecies) and between bacteria and higher organisms (inter-kingdom). The fact that QS-based communication appears to be widespread among microbes is strange, considering that explaining both cooperation and communication are two of the greatest problems in evolutionary biology. From an evolutionary perspective, intraspecies signalling can be explained using models such as kin selection, but when communication is described between species, it is more difficult to explain. It is probable that in many cases this involves QS molecules being used as 'cues' by other species as a guide to future action or as manipulating molecules whereby one species will 'coerce' a response from another. In these cases, the usage of QS molecules cannot be described as signalling. This review seeks to integrate the evolutionary literature on animal signalling with the microbiological literature on QS, and asks whether QS within bacteria is true signalling or whether these molecules are also used as cues or for the coercion of other cells. 相似文献
8.
Leah Edelstein-Keshet William R. Holmes Mark Zajac Meghan Dutot 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1629)
Many mathematical models have been proposed for the process of cell polarization. Some of these are ‘functional models’ that capture a class of dynamical behaviour, whereas others are derived from features of signalling molecules. Some mechanistic models are detailed, and therefore complex, whereas others are simplified. Each type contributes to our understanding of cell polarization. However, the huge variety at different levels of detail makes comparisons challenging. Here, we provide examples of both elementary and more detailed models for polarization. We also display how a recent mathematical method, local perturbation analysis, can provide an appropriate tool for such comparisons. This technique simplifies and speeds up the model development process by revealing the effect of model extensions, parameter variations and in silico manipulations such as knock-out or over-expression of key molecules. Finally, simulations in both one dimension and two dimensions, and particularly in deforming two-dimensional ‘cells’, can highlight behaviour not captured by traditional simulation methods. 相似文献
9.
Md. Mosharrof Hossain Sarker MengChu Zhou Pranela Rameshwar John A. Hanover 《Progress in biophysics and molecular biology》2014
Molecular and cellular biology has moved towards complete and accurate knowledge of how molecules behave in space and time. Protein is considered as the primary group of molecules responsible for mediating most physiological processes. Changes in the levels of proteins may lead to the altered function and are responsible for many diseases. This review provides a partial molecular explanation of biological force-ratio generation that may act to split protein into branches, and shows molecular functional divergence. Developing a non-reductionist theory of the cellular function in medicine is clearly not sufficient. Finding effective parameters of the models by characterizing molecular interactions becomes necessary. Protein interactivity and stability provides a basis for an integrated understanding of pathologies such diabetes. One example of how a mechanistic analysis of such physiological processes can be of value is the time-delay between mRNA and translation that can act as a fork allowing a slowdown in gene expression. 相似文献
10.
A physical model is presented to describe theoretically the temperature-dependent interactions of lipid bilayers with small molecules such as anaesthetics. Based on an earlier model, a triangular lattice in which each site is occupied by a single lipid chain is constructed and the small (anaesthetic) molecules are assumed to occupy interstitial sites in the centre of each lattice triangle. The phase characteristics of such lipid/anaesthetic mixtures are described in terms of the interaction parameters between lipid-lipid, lipid-anaesthetic and anaesthetic-anaesthetic molecules. Depending on the chemical nature of the interacting species the following three models are formulated: Model I. An interstitial model in which the only perturbation is in the head-group region of the bilayer and direct interactions between neighbouring anaesthetic molecules are taken into account. Model II. Here, only hydrophobic interactions between anaesthetics and lipids are considered. Model III. Both van der Waals' and coulombic interactions are taken into account. Phase diagrams for the three models are obtained by numerical calculation over a wide range of interaction parameters. It is shown that in all three models, lateral phase separation takes place due to the presence of anaesthetics. The heat of transition, however, is found to be virtually independent of the anaesthetic concentration. 相似文献
11.
Hybrid-cell vaccines for cancer immune therapy 总被引:5,自引:0,他引:5
Hybrid cells generated by fusing allogenic-presenting cells, such as dendritic cells, with tumor cells are a new tool in cancer
immunotherapy which are designed to enhance the immunogenicity of antigenic tumors by presenting the whole spectrum of tumor-associated
antigens, by providing the co-stimulatory molecules required for T-cell activation, and by the expression of allogenic MHC
molecules for recruitment and activation of T-cell help. This approach has been successfully tested in animal models as well
as in clinical phaseI/II trials with various tumors. Besides clinical repsonses, induction of tumor-specific cytolytic T-cells
were observed. The electrofusion protocol described here has the advantage of high fusion efficiency, high hybrid-cell viability,
as well as high reproducibility, and can be used for various tumor cell types after minor adjustments are made to the instrument
settings in order to process large numbers of dendritic cells with consistent efficiencies. 相似文献
12.
Lee AG 《Biochemical Society transactions》2011,39(3):761-766
Intrinsic membrane proteins are solvated by a shell of lipid molecules interacting with the membrane-penetrating surface of the protein; these lipid molecules are referred to as annular lipids. Lipid molecules are also found bound between transmembrane α-helices; these are referred to as non-annular lipids. Annular lipid binding constants depend on fatty acyl chain length, but the dependence is less than expected from models based on distortion of the lipid bilayer alone. This suggests that hydrophobic matching between a membrane protein and the surrounding lipid bilayer involves some distortion of the transmembrane α-helical bundle found in most membrane proteins, explaining the importance of bilayer thickness for membrane protein function. Annular lipid binding constants also depend on the structure of the polar headgroup region of the lipid, and hotspots for binding anionic lipids have been detected on some membrane proteins; binding of anionic lipid molecules to these hotspots can be functionally important. Binding of anionic lipids to non-annular sites on membrane proteins such as the potassium channel KcsA can also be important for function. It is argued that the packing preferences of the membrane-spanning α-helices in a membrane protein result in a structure that matches nicely with that of the surrounding lipid bilayer, so that lipid and protein can meet without either having to change very much. 相似文献
13.
Protein folding studied by single-molecule FRET 总被引:5,自引:1,他引:4
14.
15.
Ion channels may be formed by self-assembly of amphipathic α-helical peptides into parallel helix bundles. The transbilayer pores formed by such peptides contain extended columns of
water molecules, the properties of which may differ from those of water in its bulk state. The de novo designed peptides of
DeGrado et al., which contain only leucine and serine residues, are considered as a simple example of such channels. Molecular
dynamics simulations of peptide helix bundles with water molecules within and at the mouths of their pores are used to refine
such models and to investigate the properties of intra-pore water. The translational and rotational mobility of water molecules
within the pores are reduced relative to bulk water. Furthermore, intra-pore waters orient themselves with their dipoles anti-parallel
to the helix dipoles, as do the hydroxyl groups of serine residues. Comparison of approximate predictions of ionic conductances
with experimental values provides support for the validity of these models.
Received: 23 April 1996 / Accepted: 7 August 1996 相似文献
16.
Conformational analysis of single DNA molecules undergoing entropically induced motion in nanochannels
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We have used the interface between a nanochannel and a microchannel as a tool for applying controlled forces on a DNA molecule. A molecule, with a radius of gyration larger than the nanochannel width, that straddles such an interface is subject to an essentially constant entropic force, which can be balanced against other forces such as the electrophoretic force from an applied electric field. By controlling the applied field we can position the molecule as desired and observe the conformation of the molecule as it stretches, relaxes, and recoils from the nanochannel. We quantify and present models for the molecular motion in response to the entropic, electrophoretic, and frictional forces acting on it. By determining the magnitude of the drag coefficients for DNA molecules in the nanostructure, we are able to estimate the confinement-induced recoil force. Finally, we demonstrate that we can use a controlled applied field and the entropic interfacial forces to unfold molecules, which can then be manipulated and positioned in their simple extended morphology. 相似文献
17.
T cell apoptosis can be triggered by different mechanisms that lead to distinctive features such as cell shrinkage, membrane blebbing, phosphatidylserine externalization, and internucleosomal DNA fragmentation. Prevailing models for the induction of apoptosis place the cytoskeleton as a distal target of the death effector molecules ('executioners'). However, the cytoskeleton can also play a role in the induction of apoptosis as suggested by the finding that cytoskeletal disruption can induce apoptosis. The mechanism by which this occurs is unknown. Here, we report that T cell apoptosis by cytoskeletal disruption involves a protein synthesis-independent mechanism leading to up-regulation of caspase-3 protease activity and increased accessibility of active caspase-3 to its substrate. Thus, cytoskeleton integrity may regulate the subcellular compartmentalization of death effector molecules. 相似文献
18.
The division of labor between template and catalyst is a fundamental property of
all living systems: DNA stores genetic information whereas proteins function as
catalysts. The RNA world hypothesis, however, posits that, at the earlier stages
of evolution, RNA acted as both template and catalyst. Why would such division
of labor evolve in the RNA world? We investigated the evolution of DNA-like
molecules, i.e. molecules that can function only as template, in minimal
computational models of RNA replicator systems. In the models, RNA can function
as both template-directed polymerase and template, whereas DNA can function only
as template. Two classes of models were explored. In the surface models,
replicators are attached to surfaces with finite diffusion. In the compartment
models, replicators are compartmentalized by vesicle-like boundaries. Both
models displayed the evolution of DNA and the ensuing division of labor between
templates and catalysts. In the surface model, DNA provides the advantage of
greater resistance against parasitic templates. However, this advantage is at
least partially offset by the disadvantage of slower multiplication due to the
increased complexity of the replication cycle. In the compartment model, DNA can
significantly delay the intra-compartment evolution of RNA towards catalytic
deterioration. These results are explained in terms of the trade-off between
template and catalyst that is inherent in RNA-only replication cycles: DNA
releases RNA from this trade-off by making it unnecessary for RNA to serve as
template and so rendering the system more resistant against evolving parasitism.
Our analysis of these simple models suggests that the lack of catalytic activity
in DNA by itself can generate a sufficient selective advantage for RNA
replicator systems to produce DNA. Given the widespread notion that DNA evolved
owing to its superior chemical properties as a template, this study offers a
novel insight into the evolutionary origin of DNA. 相似文献
19.
Hlavacek WS Faeder JR Blinov ML Perelson AS Goldstein B 《Biotechnology and bioengineering》2003,84(7):783-794
Many activities of cells are controlled by cell-surface receptors, which in response to ligands, trigger intracellular signaling reactions that elicit cellular responses. A hallmark of these signaling reactions is the reversible nucleation of multicomponent complexes, which typically begin to assemble when ligand-receptor binding allows an enzyme, often a kinase, to create docking sites for signaling molecules through chemical modifications, such as tyrosine phosphorylation. One function of such docking sites is the co-localization of enzymes with their substrates, which can enhance both enzyme activity and specificity. The directed assembly of complexes can also influence the sensitivity of cellular responses to ligand-receptor binding kinetics and determine whether a cellular response is up- or downregulated in response to a ligand stimulus. The full functional implications of ligand-stimulated complex formation are difficult to discern intuitively. Complex formation is governed by conditional interactions among multivalent signaling molecules and influenced by quantitative properties of both the components in a system and the system itself. Even a simple list of the complexes that can potentially form in response to a ligand stimulus is problematic because of the number of ways signaling molecules can be modified and combined. Here, we review the role of multicomponent complexes in signal transduction and advocate the use of mathematical models that incorporate detail at the level of molecular domains to study this important aspect of cellular signaling. 相似文献
20.
The MHC class I molecule, HLA-B27 can be expressed as a number of non-conventional forms, in addition to conventional HLA-B27 heterodimers presenting peptide. This has lead to new avenues of research to explain the association of this molecule with SpA. Surprisingly, HLA-B27 transgenic animal models implicated CD4+ T cells, which conventionally interact with MHC class II molecules, not MHC class I molecules, in the pathogenesis of SpA. One hypothesis to explain these finding is that non-conventional forms of HLA-B27, specifically HLA-B27 homodimers, might mimic MHC class II molecules and be recognised by CD4+ T cells. We investigated whether CD4+ T cells from AS patients can interact with HLA-B27, discovering that indeed CD4+ T cells can interact with various forms of HLA-B27. Here we discuss how such interactions between HLA-B27 and CD4+ T cells could occur in vivo and potential contributions of such interactions to the pathogenesis of SpA. 相似文献