UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and disparate types of data attendant with cutting-edge experimental methods, while providing advanced options for high-quality rendering (interactive ambient occlusion, reliable molecular surface calculations, etc.) and professional approaches to software design and distribution. This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility. ChimeraX is free for noncommercial use and is available from http://www.rbvi.ucsf.edu/chimerax/ for Windows, Mac, and Linux.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/pro.3235

UCSF ChimeraX: Meeting modern challenges in visualization and analysis.

Molecular docking has become an increasingly important tool for drug discovery. In this review, we present a brief introduction of the available molecular docking methods, and their development and applications in drug discovery. The relevant basic theories, including sampling algorithms and scoring functions, are summarized. The differences in and performance of available docking software are also discussed. Flexible receptor molecular docking approaches, especially those including backbone flexibility in receptors, are a challenge for available docking methods. A recently developed Local Move Monte Carlo (LMMC) based approach is introduced as a potential solution to flexible receptor docking problems. Three application examples of molecular docking approaches for drug discovery are provided.

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Molecular docking: a powerful approach for structure-based drug discovery.

Virtual molecular screening is used to dock small-molecule libraries to a macromolecule in order to find lead compounds with desired biological function. This in silico method is well known for its application in computer-aided drug design. This chapter describes how to perform small-molecule virtual screening by docking with PyRx, which is open-source software with an intuitive user interface that runs on all major operating systems (Linux, Windows, and Mac OS). Specific steps for using PyRx, as well as considerations for data preparation, docking, and data analysis, are also described.

Small-Molecule Library Screening by Docking with PyRx

Docking of small molecule compounds into the binding site of a receptor and estimating the binding affinity of the complex is an important part of the structure-based drug design process. For a thorough understanding of the structural principles that determine the strength of a protein/ligand complex both, an accurate and fast docking protocol and the ability to visualize binding geometries and interactions are mandatory. Here we present an interface between the popular molecular graphics system PyMOL and the molecular docking suites Autodock and Vina and demonstrate how the combination of docking and visualization can aid structure-based drug design efforts.

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Ligand docking and binding site analysis with PyMOL and Autodock/Vina.

The initial stage of host cell infection by influenza A viruses (IAV) is mediated through interaction of the viral haemagglutinin (HA) with cell surface glycans. The binding requirement of IAVs for Galβ(1,4)Glc/ GlcNAc (lactose/lactosamine) glycans with a terminal α(2,6)-linked (human receptors) or α(2,3)-linked (avian receptors) N-acetylneuraminic residue commonly found on N-glycans, is well-established. However the role and significance of sialylated Galβ(1,3)GalNAc (core 1) epitopes that are typical O-glycoforms in influenza virus pathogenesis remains poorly detailed. Here we report a multidisciplinary study using NMR spectroscopy, virus neutralization assays and molecular modelling, into the potential for IAV to engage sialyl-Galβ(1,3)GalNAc O-glycoforms for cell attachment. H5 containing virus like particles (VLPs) derived from an H5N1 avian IAV strain show a significant involvement of the O-glycan-specific GalNAc residue, coordinated by a EQTKLY motif conserved in highly pathogenic avian influenza (HPAI) strains. Notably, human pandemic H1N1 influenza viruses shift the preference from 'human-like' α(2,6)-linkages in sialylated Galβ(1,4)Glc/GlcNAc fragments to 'avian-like' α(2,3)-linkages in sialylated Galβ(1,3)GalNAc without involvement of the GalNAc residue. Overall, our study suggests that sialylated Galβ(1,3)GalNAc as O-glycan core 1 glycoforms are involved in the influenza A virus life cycle and play a particularly crucial role during infection of HPAI strains.

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Unravelling the Role of O-glycans in Influenza A Virus Infection

AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.

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AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading

R1ρ Relaxation outside of the Fast-Exchange Limit

Theoretical study of R1ρ rotating-frame and R2 free-precession relaxation in the presence of n-site chemical exchange

Temperature-dependent dynamics of the villin headpiece helical subdomain, an unusually small thermostable protein.

Approximate expressions for the NMR spin relaxation rate constant in the rotating frame of reference R 1ρ are derived for two-site chemical exchange by consideration of the evolution of the average density operator using the stochastic Liouville equation. R 1ρ is obtained as a linearized approximation to the largest (least negative) eigenvalue of the matrix describing the evolution of the average density operator in the long-term limit. The expressions obtained are more accurate than existing expressions when exchange is not fast and the populations of the exchanging sites are close to equal. The new expressions for R 1ρ facilitate the interpretation of chemical exchange phenomena in proteins and other biological macromolecules.

Oleg Trott

Papers

AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading

R1ρ Relaxation outside of the Fast-Exchange Limit

Theoretical study of R1ρ rotating-frame and R2 free-precession relaxation in the presence of n-site chemical exchange

Temperature-dependent dynamics of the villin headpiece helical subdomain, an unusually small thermostable protein.

An average-magnetization analysis of R 1ρ relaxation outside of the fast exchange limit