Modulation of Human Hsp90α Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain

Abstract

Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking. We probe the open conformation of human Hsp90α for druggable sites that overlap with these allosteric control elements, and identify three putative natural compound allosteric modulators: Cephalostatin 17, 20(29)-Lupene-3β-isoferulate and 3'-Bromorubrolide F. We assess the allosteric potential of these ligands by examining their effect on the conformational dynamics of the protein. We find evidence for the selective allosteric activation and inhibition of Hsp90's conformational transition toward the closed state in response to ligand binding and shed valuable insight to further the understanding of allosteric drug design and Hsp90's complex allosteric mechanism of action.

New Insights into the Effect of Residue Mutations on the Rotavirus VP1 Function Using Molecular Dynamic Simulations

“…For highly dynamic proteins, it was reported strong positive correlation between L and RMSF [36,37], and moderate and weak inverse correlation between BC and L or RMSF, respectively [37]. These findings were partially supported in the present study by calculating the pairwise Pearson's correlation coefficient of average L, average BC, and RMSF for each VP1 (which was not certified by peer review) is the author/funder.…”

MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics

“…Pairwise communication propensity is computed as the mean-square fluctuation of the inter-residue distance, using C α atoms. It relies on the fact that intra-protein signal transduction events are directly related to the distance fluctuations of communicating atoms [26] , [31] . Low CP values correspond to more efficient (faster) communication compared to larger values.…”

“…Both MD-TASK and MODE-TASK have been highly utilized to mine protein dynamics by offering a series of novel approaches that have demonstrated their applicability in a growing number of cases [6] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] . Although both software suites are relatively easy to use, the required technical knowledge and software dependencies may act as a hurdle against more widespread usage of the tools and techniques, due to the diversity of operating systems and the relatively fast-evolving Python libraries.…”

“…The need for additional software, complex dependencies and command line expertise is greatly reduced. MDM-TASK-web includes new features such as additional network centrality metrics for both DRN and Residue Interaction Network (RIN) centrality calculations from single structures, a communication propensity (CP) tool [26] , [31] ⁠, an aggregator of weighted residue contact maps, comparative ED, an ANM workflow, NMA from MD and integrated 2D/3D visualization. All tools have been ported to Python 3.…”

MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics

“…The need for additional software, complex dependencies and command line expertise are greatly reduced. MDM-TASK-web includes new features such as additional DRN metrics, a communication propensity (CP) tool (Chennubhotla and Bahar, 2007; Penkler and Tastan Bishop, 2019), an aggregator of residue contact maps, comparative essential dynamics (ED), an anisotropic network model (ANM) workflow, and integrated 2D & 3D visualization. All tools have been ported to Python 3.…”