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NTPs compete in the active site of RNA polymerases I and II NTP 在 RNA 聚合酶 I 和 II 的活性位点上相互竞争
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-03 DOI: 10.1016/j.bpc.2024.107302

Eukaryotes express at least three RNA polymerases (Pols) carry out transcription, while bacteria and archaea use only one. Using transient state kinetics, we have extensively examined and compared the kinetics of both single and multi-nucleotide additions catalyzed by the three Pols. In single nucleotide addition experiments we have observed unexpected extension products beyond one incorporation, which can be attributed to misincorporation, the presence of nearly undetectable amounts of contaminating NTPs, or a mixture of the two. Here we report the development and validation of an analysis strategy to account for the presence of unexpected extension products, when they occur. Using this approach, we uncovered evidence showing that non-cognate nucleotide, thermodynamically, competes with cognate nucleotide for the active site within the elongation complex of Pol I, ΔA12 Pol I, and Pol II. This observation is unexpected because base pairing interactions provide favorable energetics for selectivity and competitive binding indicates that the affinities of cognate and non-cognate nucleotides are within an order of magnitude. Thus, we show that application of our approach will allow for the extraction of additional information that reports on the energetics of nucleotide entry and selectivity.

真核生物至少表达三种 RNA 聚合酶(Pols)进行转录,而细菌和古细菌只使用一种。利用瞬态动力学,我们对三种 Pols 催化的单核苷酸和多核苷酸添加的动力学进行了广泛的研究和比较。在单核苷酸加成实验中,我们观察到了超出一次加成的意外延伸产物,这可能是由于误加成、存在几乎检测不到的污染 NTP 或两者的混合所致。在此,我们报告了一种分析策略的开发和验证情况,该策略可在出现意外延伸产物时对其进行解释。利用这种方法,我们发现有证据表明,在 Pol I、ΔA12 Pol I 和 Pol II 的延伸复合体中,非识别核苷酸在热力学上与识别核苷酸竞争活性位点。这一观察结果出乎意料,因为碱基配对相互作用为选择性提供了有利的能量,而竞争性结合表明同源核苷酸和非同源核苷酸的亲和力在一个数量级之内。因此,我们的研究表明,应用我们的方法可以提取更多信息,报告核苷酸进入和选择性的能量学。
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引用次数: 0
Tailoring solid-state DNP methods to the study of α-synuclein LLPS 调整固态 DNP 方法以研究 α-synuclein LLPS。
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-30 DOI: 10.1016/j.bpc.2024.107303

Dynamic Nuclear Polarization (DNP) is a technique that leverages the quantum sensing capability of electron spins to enhance the sensitivity of nuclear magnetic resonance (NMR) signals, especially for insensitive samples. Glassing agents play a crucial role in the DNP process by facilitating the transfer of polarization from the unpaired electron spins to the nuclear spins along with cryoprotection of biomolecules. DNPjuice comprising of glycerol-d8/D2O/H2O has been extensively used for this purpose over the past two decades. Polyethylene glycol (PEG), also used as a cryoprotectant, is often used as a crowding agent in experimental setups to mimic cellular conditions, particularly the invitro preparation of liquid-liquid phase separated (LLPS) condensates. In this study, we investigate the efficacy of PEG as an alternative to glycerol in the DNP juice, critical for signal enhancement. The modified DNP matrix leads to high DNP enhancement which enables direct study of LLPS condensates by solid-state DNP methods without adding any external constituents. An indirect advantage of employing PEG is that the PEG signals appear at 72.5 ppm and are relatively well-separated from the aliphatic region of the protein spectra. Large cross-effect DNP enhancement is attained for 13C-glycine by employing the PEG-water mixture as a glassing agent and ASYMPOL-POK as the state-of-art polarizing agent, without any deuteration. The DNP enhancement and the buildup rates are similar to results obtained with DNP juice, conforming to that PEG serves as a good candidate for both inducing crowding and glassing agent in the study of LLPS.

动态核极化(DNP)是一种利用电子自旋的量子感应能力来提高核磁共振(NMR)信号灵敏度的技术,尤其适用于不敏感的样品。玻璃化剂在 DNP 过程中起着至关重要的作用,它可以促进极化从未配对的电子自旋转移到核自旋,同时对生物大分子进行低温保护。在过去的二十年中,由甘油-d8/D2O/H2O 组成的 DNP 胶液已被广泛用于这一目的。聚乙二醇(PEG)也被用作低温保护剂,在模拟细胞条件的实验装置中,尤其是在体外制备液-液相分离(LLPS)冷凝物时,它经常被用作拥挤剂。在本研究中,我们研究了 PEG 在 DNP 果汁中替代甘油的功效,这对增强信号至关重要。改良后的 DNP 基质具有很高的 DNP 增强效果,因此可以通过固态 DNP 方法直接研究 LLPS 冷凝物,而无需添加任何外部成分。使用 PEG 的一个间接优势是 PEG 信号出现在 ∼72.5 ppm 处,与蛋白质光谱的脂肪族区域相对分离。使用 PEG 与水的混合物作为玻璃化剂,ASYMPOL-POK 作为最先进的极化剂,在不进行任何氘化的情况下,13C-甘氨酸的 DNP 得到了很大的交叉效应增强。DNP 增强效果和累积率与使用 DNP 果汁得到的结果相似,这表明在 LLPS 研究中,PEG 既是诱导拥挤的理想候选物质,也是玻璃化剂。
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引用次数: 0
Bridging in silico and in vitro perspectives to unravel molecular mechanisms underlying the inhibition of β-glucuronidase by coumarins from Hibiscus trionum 打通硅学和体外研究的视角,揭示芙蓉三香豆素抑制β-葡糖醛酸酶的分子机制
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1016/j.bpc.2024.107304

Unraveling the intricacies of β-glucuronidase inhibition is pivotal for developing effective strategies in applications specific to gastrointestinal health and drug metabolism. Our study investigated the efficacy of some Hibiscus trionum phytochemicals as β-glucuronidase inhibitors. The results showed that cleomiscosin A and mansonone H emerged as the most potent inhibitors, with IC50 values of 3.97 ± 0.35 μM and 10.32 ± 1.85 μM, respectively. Mechanistic analysis of β-glucuronidase inhibition indicated that cleomiscosin A and the reference drug EGCG displayed a mixed inhibition mode against β-glucuronidase, while mansonone H exhibited noncompetitive inhibition against β-glucuronidase. Docking studies revealed that cleomiscosin A and mansonone H exhibited the lowest binding affinities, occupying the same site as EGCG, and engaged significant key residues in their binding mechanisms. Using a 30 ns molecular dynamics (MD) simulation, we explored the interaction dynamics of isolated compounds with β-glucuronidase. Analysis of various MD parameters showed that cleomiscosin A and mansonone H exhibited consistent trajectories and significant energy stabilization with β-glucuronidase. These computational insights complemented experimental findings, underscoring the potential of cleomiscosin A and mansonone H as β-glucuronidase inhibitors.

揭示β-葡糖醛酸酶抑制作用的复杂性对于开发胃肠道健康和药物代谢特定应用领域的有效策略至关重要。我们的研究调查了一些芙蓉三叶草植物化学物质作为β-葡糖醛酸酶抑制剂的功效。结果表明,cleomiscosin A 和 mansonone H 是最有效的抑制剂,其 IC50 值分别为 3.97 ± 0.35 μM 和 10.32 ± 1.85 μM。对β-葡萄糖醛酸酶抑制作用的机理分析表明,裂袂木香苷 A 和参考药物 EGCG 对β-葡萄糖醛酸酶具有混合抑制作用,而曼松酮 H 对β-葡萄糖醛酸酶具有非竞争性抑制作用。Docking 研究表明,cleomiscosin A 和 mansonone H 与 EGCG 的结合亲和力最低,占据了相同的位点,并且在其结合机制中参与了重要的关键残基。利用 30 ns 分子动力学(MD)模拟,我们探索了分离化合物与 β-葡萄糖醛酸酶的相互作用动力学。对各种 MD 参数的分析表明,cleomiscosin A 和 mansonone H 与 β-葡萄糖醛酸酶表现出一致的轨迹和显著的能量稳定。这些计算见解与实验结果相辅相成,凸显了裂米苷 A 和曼松酮 H 作为 β-葡萄糖醛酸酶抑制剂的潜力。
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引用次数: 0
Erratum to “Isolated auto-citrullinated regions of PADI4 associate to the intact protein without altering their disordered conformation” [Biophysical Chemistry …(2024) …] 对 "PADI4 的分离自瓜氨酸区与完整蛋白质结合而不改变其无序构象 "的勘误 [Biophysical Chemistry ...(2024) ...]..
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1016/j.bpc.2024.107295
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引用次数: 0
Computational and in vitro binding studies of theophylline against phosphodiesterases functioning in sperm in presence and absence of pentoxifylline 茶碱与精子中存在和不存在的磷酸二酯酶的计算和体外结合研究
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-14 DOI: 10.1016/j.bpc.2024.107294

Fertility is a result of a synergy among the sperm's various functions including capacitation, motility, chemotaxis, acrosome reaction, and, finally, the fertilization of the oocyte. Subpar motility is the most common cause of infertility in males. Cyclic adenosine monophosphate (cAMP) signalling underlies motility and is depleted by the phosphodiesterases (PDEs) in sperm, such as PDE10A, PDE1, and PDE4. Therefore, the PDE inhibitor (PDEI) category of fertility drugs aim to enhance motility in assisted reproduction technologies (ARTs) through inhibition of PDEs, though they might have adverse effects on other physiological variables. For example, the popular drug pentoxifylline (PTX), widely used in ARTs, improves motility but causes premature acrosome reaction and exerts toxicity on the fertilized oocyte. Another xanthine-derived drug, theophylline (TP), has been repurposed for treating infertility, but its mechanism of PDE inhibition remains unexplored. Here, using biophysical and computational approaches, we identified that TP binds to the same binding pocket as PTX with higher affinity than PTX. We also found that PTX and TP co-bind to the same binding pocket, but at different sites.

生育能力是精子各种功能协同作用的结果,这些功能包括获能、运动、趋化、顶体反应,以及最终使卵细胞受精。精子活力不足是导致男性不育的最常见原因。环磷酸腺苷(cAMP)信号是精子活力的基础,而精子中的磷酸二酯酶(PDEs),如 PDE10A、PDE1 和 PDE4,会耗尽环磷酸腺苷(cAMP)信号。因此,PDE 抑制剂(PDEI)类生育药物旨在通过抑制 PDEs 来提高辅助生殖技术(ART)中的精子活力,尽管它们可能会对其他生理变量产生不利影响。例如,在辅助生殖技术中广泛使用的常用药喷托维林(PTX)可提高运动能力,但会导致过早的顶体反应,并对受精卵细胞产生毒性。另一种黄嘌呤衍生药物茶碱(TP)已被重新用于治疗不孕症,但其抑制PDE的机制仍未被探索。在此,我们使用生物物理和计算方法确定了 TP 与 PTX 结合到相同的结合口袋,其亲和力高于 PTX。我们还发现 PTX 和 TP 共同结合到同一个结合袋中,但结合的位点不同。
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引用次数: 0
Calcium ions do not influence the Aβ(25–35) triggered morphological changes of lipid membranes 钙离子不会影响 Aβ(25-35)引发的脂膜形态变化。
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1016/j.bpc.2024.107292

We have studied the effect of calcium ions (Ca2+) at various concentrations on the structure of lipid vesicles in the presence of amyloid-beta peptide Aβ(25–35). In particular, we have investigated the influence of calcium ions on the formation of recently documented bicelle-like structures (BLSs) emerged as a result of Aβ(25–35) triggered membrane disintegration. First, we have shown by using small-angle X-ray and neutron scattering that peptide molecules rigidify the lipid bilayer of gel phase DPPC unilamellar vesicles (ULVs), while addition of the calcium ions to the system hinders this effect of Aβ(25–35). Secondly, the Aβ(25–35) demonstrates a critical peptide concentration at which the BLSs reorganize from ULVs due to heating and cooling the samples through the lipid main phase transition temperature (Tm). However, addition of calcium ions does not affect noticeably the Aβ-induced formation of BLSs and their structural parameters, though the changes in peptide's secondary structure, e.g. the increased α-helix fraction, has been registered by circular dichroism spectroscopy. Finally, according to 31P nuclear magnetic resonance (NMR) measurements, calcium ions do not affect the lipid-peptide arrangement in BLSs and their ability to align in the magnetic field of NMR spectrometer. The influences of various concentrations of calcium ions on the lipid-peptide interactions may prove biologically important because their local concentrations vary widely in in-vivo conditions. In the present work, calcium ions were investigated as a possible tool aimed at regulating the lipid-peptide interactions that demonstrated the disruptive effect of Aβ(25–35) on lipid membranes.

我们研究了不同浓度的钙离子(Ca2+)对存在淀粉样β肽Aβ(25-35)的脂质囊泡结构的影响。特别是,我们研究了钙离子对最近记录的因淀粉样β肽Aβ(25-35)引发的膜解体而形成的双核样结构(BLSs)的影响。首先,我们利用小角 X 射线和中子散射证明,肽分子能使凝胶相 DPPC 单拉美米尔囊泡的脂质双分子层僵化,而钙离子的加入则会阻碍 Aβ(25-35)的这种作用。其次,Aβ(25-35)显示了一个临界肽浓度,在该浓度下,由于加热和冷却样品使其达到脂质主相转变温度(Tm),BLS 从 ULV 重组。然而,加入钙离子并不会明显影响 Aβ 诱导的 BLS 的形成及其结构参数,尽管圆二色谱法记录了肽二级结构的变化,如 α 螺旋部分的增加。最后,根据 31P 核磁共振(NMR)测量,钙离子不会影响 BLS 中脂肽的排列及其在 NMR 光谱仪磁场中的排列能力。不同浓度的钙离子对脂肽相互作用的影响可能具有重要的生物学意义,因为钙离子在体内的局部浓度变化很大。本研究将钙离子作为调节脂质-肽相互作用的一种可能工具进行研究,结果表明 Aβ(25-35)对脂质膜具有破坏作用。
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引用次数: 0
Enhancing amyloid beta inhibition and disintegration by natural compounds: A study utilizing spectroscopy, microscopy and cell biology 利用天然化合物增强淀粉样蛋白 beta 的抑制和分解作用:利用光谱学、显微镜和细胞生物学进行研究
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1016/j.bpc.2024.107291

Amyloid proteins and peptides play a pivotal role in the etiology of various neurodegenerative diseases, including Alzheimer's disease (AD). Synthetically designed small molecules/ peptides/ peptidomimetics show promise towards inhibition of various kinds of amyloidosis. However, exploration of compounds isolated from natural extracts having such potential is lacking. Herein, we have investigated the repurposing of a traditional Indian medicine Lasunadya Ghrita (LG) in AD. LG is traditionally used to treat gut dysregulation and mental illnesses. Various extracts of LG were obtained, characterized, and analyzed for inhibition of Aβ aggregation. Biophysical studies show that the water extract of LG (LGWE) is more potent in inhibiting Aβ peptide aggregation and defibrillation of Aβ40/Aβ42 aggregates. NMR studies showed that LGWE binds to the central hydrophobic area and C-terminal residues of Aβ40/Aβ42, thereby modulating the aggregation, and reducing cell membrane damage. Additionally, LGWE rescues Aβ toxicity in neuronal SH-SY5Y cells evident from decreases in ROS generation, membrane leakage, cellular apoptosis, and calcium dyshomeostasis. Notably, LGWE is non-toxic to neuronal cells and mouse models. Our study thus delves into the mechanistic insights of a repurposed drug LGWE with the potential to ameliorate Aβ induced neuroinflammation.

淀粉样蛋白和肽在包括阿尔茨海默病(AD)在内的各种神经退行性疾病的病因中起着关键作用。合成设计的小分子/肽/拟肽化合物有望抑制各种淀粉样变性。然而,对从天然提取物中分离出的具有这种潜力的化合物还缺乏探索。在此,我们研究了印度传统药物Lasunadya Ghrita(LG)在AD中的再利用。LG传统上用于治疗肠道失调和精神疾病。研究人员获得了 LG 的各种提取物,对其进行了表征,并分析了其对 Aβ 聚集的抑制作用。生物物理研究表明,LG 的水提取物(LGWE)在抑制 Aβ 肽聚集和 Aβ40/Aβ42 聚集的去颤方面更有效。核磁共振研究表明,LGWE 可与 Aβ40/Aβ42 的中央疏水区和 C 端残基结合,从而调节聚集,减少细胞膜损伤。此外,LGWE 还能挽救神经元 SH-SY5Y 细胞中的 Aβ 毒性,这体现在 ROS 生成、膜渗漏、细胞凋亡和钙失衡的减少上。值得注意的是,LGWE 对神经细胞和小鼠模型无毒性。因此,我们的研究深入探讨了 LGWE 这种具有改善 Aβ 诱导的神经炎症潜力的再利用药物的机理。
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引用次数: 0
Advanced applications of Nanodiscs-based platforms for antibodies discovery 基于纳米盘的抗体发现平台的高级应用。
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1016/j.bpc.2024.107290
Kristina O. Baskakova , Pavel K. Kuzmichev , Mikhail S. Karbyshev

Due to their fundamental biological importance, membrane proteins (MPs) are attractive targets for drug discovery, with cell surface receptors, transporters, ion channels, and membrane-bound enzymes being of particular interest. However, due to numerous challenges, these proteins present underutilized opportunities for discovering biotherapeutics. Antibodies hold the promise of exquisite specificity and adaptability, making them the ideal candidates for targeting complex membrane proteins. They can target specific conformations of a particular membrane protein and can be engineered into various formats. Generating specific and effective antibodies targeting these proteins is no easy task due to several factors. The antigen's design, antibody-generation strategies, lead optimization technologies, and antibody modalities can be modified to tackle these challenges. The rational employment of cutting-edge lipid nanoparticle systems for retrieving the membrane antigen has been successfully implemented to simplify the mechanism-based therapeutic antibody discovery approach. Despite the highlighted MP production challenges, this review unequivocally underscores the advantages of targeting complex membrane proteins with antibodies and designing membrane protein antigens. Selected examples of lipid nanoparticle success have been illustrated, emphasizing the potential of therapeutic antibody discovery in this regard. With further research and development, we can overcome these challenges and unlock the full potential of therapeutic antibodies directed to target complex MPs.

膜蛋白(MPs)具有重要的生物学基础,是极具吸引力的药物发现目标,其中细胞表面受体、转运体、离子通道和膜结合酶尤其令人感兴趣。然而,由于面临诸多挑战,这些蛋白质在发现生物治疗药物方面的机会尚未得到充分利用。抗体具有良好的特异性和适应性,是靶向复杂膜蛋白的理想候选物。它们可以靶向特定膜蛋白的特定构象,并可被设计成各种形式。由于多种因素的影响,要产生针对这些蛋白质的特异而有效的抗体并非易事。抗原设计、抗体生成策略、先导优化技术和抗体模式都可以通过改进来应对这些挑战。合理利用最先进的脂质纳米粒子系统来回收膜抗原,简化了基于机制的治疗性抗体发现方法,已获得成功。尽管纳米脂质颗粒的生产面临诸多挑战,本综述仍明确强调了用抗体靶向复杂膜蛋白和设计膜蛋白抗原的优势。本文列举了一些脂质纳米粒子的成功实例,强调了治疗性抗体发现在这方面的潜力。通过进一步的研究和开发,我们可以克服这些挑战,充分释放针对复杂膜蛋白的治疗性抗体的潜力。
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引用次数: 0
Authentic hSAA related with AA amyloidosis: New method of purification, folding and amyloid polymorphism 与 AA 淀粉样变性有关的真品 hSAA:纯化、折叠和淀粉样蛋白多态性的新方法
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1016/j.bpc.2024.107293
Natalya Katina , Victor Marchenkov , Yulia Lapteva , Vitalii Balobanov , Nelly Ilyina , Natalya Ryabova , Stanislav Evdokimov , Mariya Suvorina , Alexey Surin , Anatoly Glukhov

The secondary amyloidosis of humans is caused by the formation of hSAA fibrils in different organs and tissues. Until now hSAA was thought to have low amyloidogenicity in vitro and the majority of SAA aggregation experiments were done using murine protein or hSAA non-pathogenic isoforms. In this work a novel purification method for recombinant hSAA was introduced, enabling to obtain monomeric protein capable of amyloid aggregation under physiological conditions. The stability and amyloid aggregation of hSAA have been examined using a wide range of biophysical methods. It was shown that the unfolding of monomeric protein occurs through the formation of molten globule-like intermediate state. Polymorphism of hSAA amyloids was discovered to depend on the solution pH. At pH 8.5, rapid protein aggregation occurs, which leads to the formation of twisted short fibrils. Even a slight decrease of the pH to 7.8 results in delayed aggregation with the formation of long straight amyloids composed of laterally associated protofilaments. Limited proteolysis experiments have shown that full-length hSAA is involved in the formation of intermolecular interactions in both amyloid polymorphs. The results obtained, and the experimental approach used in this study can serve as a basis for further research on the mechanism of authentic hSAA amyloid formation.

人类的继发性淀粉样变性是由 hSAA 纤维在不同器官和组织中的形成引起的。迄今为止,人们一直认为 hSAA 在体外的淀粉样蛋白致性较低,而且大多数 SAA 聚集实验都是使用鼠蛋白或 hSAA 非致病异构体进行的。在这项工作中,引入了一种新的重组 hSAA 纯化方法,从而获得了能够在生理条件下发生淀粉样聚集的单体蛋白。使用多种生物物理方法对 hSAA 的稳定性和淀粉样聚集进行了研究。研究表明,单体蛋白的解折是通过形成熔融球状中间状态来实现的。研究发现,hSAA淀粉样蛋白的多态性取决于溶液的pH值。在 pH 值为 8.5 时,蛋白质迅速聚集,形成扭曲的短纤维。即使 pH 值稍微降低到 7.8,也会导致延迟聚集,形成由横向关联的原丝组成的长直淀粉样。有限的蛋白水解实验表明,全长 hSAA 参与了两种淀粉样多态体中分子间相互作用的形成。本研究中获得的结果和使用的实验方法可作为进一步研究真正的 hSAA 淀粉样蛋白形成机制的基础。
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引用次数: 0
Probing the energy landscape of the lipid interactions of the Serotonin1A receptor 探究血清素 1A 受体脂质相互作用的能量分布。
IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-03 DOI: 10.1016/j.bpc.2024.107289
Madhura Mohole , Amit Naglekar , Durba Sengupta , Amitabha Chattopadhyay

G protein-coupled receptors (GPCRs) are lipid-regulated transmembrane proteins that play a central role in cell signaling and pharmacology. Although the role of membrane lipids in GPCR function is well established, the underlying GPCR-lipid interactions have not been thermodynamically characterized due to the complexity of these interactions. In this work, we estimate the energetics and dynamics of lipid association from coarse-grain simulations of the serotonin1A receptor embedded in a complex membrane. We show that lipids bind to the receptor with varying energetics of 1–4 kT, and timescales of 1–10 μs. The most favorable energetics and longest residence times are observed for cholesterol, glycosphingolipid GM1, phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Multi-exponential fitting of the contact probability suggests distinct dynamic regimes, corresponding to ps, ns and μs timescales, that we correlate with the annular, intermediate and non-annular lipid sites. The timescales of lipid binding correspond to high barrier heights, despite their relatively weaker energetics. Our results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.

G 蛋白偶联受体(GPCR)是受脂质调控的跨膜蛋白,在细胞信号传导和药理学中发挥着核心作用。虽然膜脂质在 GPCR 功能中的作用已得到公认,但由于 GPCR 与脂质相互作用的复杂性,尚未从热力学角度对这些相互作用进行表征。在这项研究中,我们通过对嵌入复杂膜中的血清素 1A 受体进行粗粒度模拟,估算了脂质结合的能量学和动力学。我们发现,脂质与受体结合的能量为 1-4 kT,时间尺度为 1-10 μs。胆固醇、糖蛋白脂质 GM1、磷脂酰乙醇胺(PE)和磷脂酰丝氨酸(PS)脂质的能量最高,停留时间最长。接触概率的多指数拟合表明了不同的动态机制,分别对应于 ps、ns 和 μs 时间尺度,我们将其与环状、中间和非环状脂质位点相关联。尽管脂质结合的能量相对较弱,但其时间尺度却与高阻抗高度相对应。我们的研究结果突出表明,GPCR-脂质相互作用是由热力学相互作用和脂质结合的动力学特征共同驱动的。
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引用次数: 0
期刊
Biophysical chemistry
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