Multi-drug resistance profile of PR20 HIV-1 protease is attributed to distorted conformational and drug binding landscape: molecular dynamics insights

The PR20 HIV-1 protease, a variant with 20 mutations, exhibits high levels of multi-drug resistance; however, to date, there has been no report detailing the impact of these 20 mutations on the conformational and drug binding landscape at a molecular level. In this report, we demonstrate the first account of a comprehensive study designed to elaborate on the impact of these mutations on the dynamic features as well as drug binding and resistance profile, using extensive molecular dynamics analyses. Comparative MD simulations for the wild-type and PR20 HIV proteases, starting from bound and unbound conformations in each case, were performed. Results showed that the apo conformation of the PR20 variant of the HIV protease displayed a tendency to remain in the open conformation for a longer period of time when compared to the wild type. This led to a phenomena in which the inhibitor seated at the active site of PR20 tends to diffuse away from the binding site leading to a significant change in inhibitor–protein association. Calculating the per-residue fluctuation (RMSF) and radius of gyration, further validated these findings. MM/GBSA showed that the occurrence of 20 mutations led to a drop in the calculated binding free energies (ΔG_bind) by ~25.17 kcal/mol and ~5 kcal/mol for p2-NC, a natural peptide substrate, and darunavir, respectively, when compared to wild type. Furthermore, the residue interaction network showed a diminished inter-residue hydrogen bond network and changes in inter-residue connections as a result of these mutations. The increased conformational flexibility in PR20 as a result of loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces led to a loss of protease grip on ligand. It is interesting to note that the difference in conformational flexibility between PR20 and WT conformations was much higher in the case of substrate-bound conformation as compared to DRV. Thus, developing analogues of DRV by retaining its key pharmacophore features will be the way forward in the search for novel protease inhibitors against multi-drug resistant strains.     

Emergence of network structure due to spike-timing-dependent plasticity in recurrent neuronal networks. I. Input selectivity–strengthening correlated input pathways

Spike-timing-dependent plasticity (STDP) determines the evolution of the synaptic weights according to their pre- and post-synaptic activity, which in turn changes the neuronal activity. In this paper, we extend previous studies of input selectivity induced by (STDP) for single neurons to the biologically interesting case of a neuronal network with fixed recurrent connections and plastic connections from external pools of input neurons. We use a theoretical framework based on the Poisson neuron model to analytically describe the network dynamics (firing rates and spike-time correlations) and thus the evolution of the synaptic weights. This framework incorporates the time course of the post-synaptic potentials and synaptic delays. Our analysis focuses on the asymptotic states of a network stimulated by two homogeneous pools of “steady” inputs, namely Poisson spike trains which have fixed firing rates and spike-time correlations. The (STDP) model extends rate-based learning in that it can implement, at the same time, both a stabilization of the individual neuron firing rates and a slower weight specialization depending on the input spike-time correlations. When one input pathway has stronger within-pool correlations, the resulting synaptic dynamics induced by (STDP) are shown to be similar to those arising in the case of a purely feed-forward network: the weights from the more correlated inputs are potentiated at the expense of the remaining input connections.     

基于GIS的广州市中心城区城市森林可达性分析

城市森林是城市中主要的生态功能景观,已经成为城市生态环境建设的主体。基于居民方便获取城市森林服务的要求,根据大型城市森林斑块、道路网和街区单元数据,利用ArcGIS9.2的Network Analyst工具,分析了广州市中心城区在2km步行距离内街区单元到达城市森林斑块的可达性以及城市森林斑块的承载力,并结合航片解译的树冠覆盖数据对具有不同可达性的街区单元进行了分析。分析结果表明：广州中心城区的外环高速以内的区域范围,分别有73%、46%和18%的的街区单元在步行2km、1km和0.5km距离内能够到达大型城市森林绿地斑块。从街区单元的行政归属看,以越秀区的街区可达性最好,而海珠区和原芳村区的街区可达性较差。研究范围内,0.5km内不能到达大型城市森林斑块且树冠覆盖超过30%的街区类型中,以公共管理单位类型为主,单位绿化对于树冠覆盖的贡献率大;而绝大多数以住宅类型为主的街区单元的树冠覆盖率低于10%,其中64%的街区树冠覆盖率低于5%。以街区单元为基本对象进行可达性度量,分析城市森林斑块现状分布和服务状况,并结合其树冠覆盖特征,可以明确需要重点关注区域的空间分布,可为广州市在较小尺度上的城市森林空间布局优化提供参考。     

河网地区小城镇街尘的粒径分布与多环芳烃污染

街尘是重要的环境介质,其携带的污染物在城镇化过程中对河网地区的水环境构成了一定的威胁。以杭嘉湖平原河网地区饮用水水源河流上游典型小城镇的街尘为研究对象,对街尘、河道沉积物、地表径流以及降雨前后地表水中的多环芳烃进行测定。在对不同粒径街尘中多环芳烃浓度的测定中发现,粒径为<63、125-63、250-125和900-250 μm街尘中多环芳烃的平均含量分别为7261、5835、4660和2909μg/kg。小粒径的街尘颗粒含有较高的多环芳烃浓度,较小的密度,并且较难清扫,造成了小粒径街尘易被雨水冲刷随地表径流进入河网水体。在对两场降雨的地表径流中多环芳烃检测发现,颗粒态的多环芳烃分别占总浓度的95%和94%。地表径流过程增加了受纳水体中多环芳烃浓度的43%-62%,其中超过50%的增加表现为颗粒态。在对不同河段沉积物、地表径流中颗粒物和不同粒径街尘中多环芳烃浓度的风险评价中发现,小粒径街尘和地表径流中颗粒物中多环芳烃的浓度相接近并具有较高的生态风险,城镇段河道沉积物较次之。由于河网地区的特殊的水文条件和景观空间格局特征,地表径流沉积物在进入河网水体后易原位沉积,造成了河道沉积物城镇段有较高的多环芳烃浓度。