Predicting biomolecular binding kinetics: A review

Biomolecular binding kinetics including the association (kon) and dissociation (koff) rates are critical parameters for therapeutic design of small-molecule drugs, peptides and antibodies. Notably, drug molecule residence time or dissociation rate has been shown to correlate with their efficacies better than binding affinities. A wide range of modeling approaches including quantitative structure-kinetic relationship models, Molecular Dynamics simulations, enhanced sampling and Machine Learning have been developed to explore biomolecular binding and dissociation mechanisms and predict binding kinetic rates. Here, we review recent advances in computational modeling of biomolecular binding kinetics, with an outlook for future improvements

Studying Dynamics by Magic-Angle Spinning Solid-State NMR Spectroscopy: Principles and Applications to Biomolecules

International audienceMagic-angle spinning solid-state NMR spectroscopy is an important technique to study mo- lecular structure, dynamics and interactions, and is rapidly gaining importance in biomolecu- lar sciences. Here we provide an overview of experimental approaches to study molecular dy- namics by MAS solid-state NMR, with an emphasis on the underlying theoretical concepts and differences of MAS solid-state NMR compared to solution-state NMR. The theoretical foundations of nuclear spin relaxation are revisited, focusing on the particularities of spin re- laxation in solid samples under magic-angle spinning. We discuss the range of validity of Redfield theory, as well as the inherent multi-exponential behavior of relaxation in solids. Ex- perimental challenges for measuring relaxation parameters in MAS solid-state NMR and a few recently proposed relaxation approaches are discussed, which provide information about time scales and amplitudes of motions ranging from picoseconds to milliseconds. We also discuss the theoretical basis and experimental measurements of anisotropic interactions (chemical-shift anisotropies, dipolar and quadrupolar couplings), which give direct infor- mation about the amplitude of motions. The potential of combining relaxation data with such measurements of dynamically-averaged anisotropic interactions is discussed. Although the focus of this review is on the theoretical foundations of dynamics studies rather than their ap- plication, we close by discussing a small number of recent dynamics studies, where the dy- namic properties of proteins in crystals are compared to those in solution

Determining Peptide Partitioning Properties via Computer Simulation

The transfer of polypeptide segments into lipid bilayers to form transmembrane helices represents the crucial first step in cellular membrane protein folding and assembly. This process is driven by complex and poorly understood atomic interactions of peptides with the lipid bilayer environment. The lack of suitable experimental techniques that can resolve these processes both at atomic resolution and nanosecond timescales has spurred the development of computational techniques. In this review, we summarize the significant progress achieved in the last few years in elucidating the partitioning of peptides into lipid bilayer membranes using atomic detail molecular dynamics simulations. Indeed, partitioning simulations can now provide a wealth of structural and dynamic information. Furthermore, we show that peptide-induced bilayer distortions, insertion pathways, transfer free energies, and kinetic insertion barriers are now accurate enough to complement experiments. Further advances in simulation methods and force field parameter accuracy promise to turn molecular dynamics simulations into a powerful tool for investigating a wide range of membrane active peptide phenomena

Nonosecond Pulsed Electric Field Induced Changes in Dielectric Properties of Biological Cells

Nanosecond pulsed electric field induced biological effects have been a focus of research interests since the new millennium. Promising biomedical applications, e.g. tumor treatment and wound healing, are emerging based on this principle. Although the exact mechanisms behind the nanosecond pulse-cell interactions are not completely understood yet, it is generally believed that charging along the cell membranes (including intracellular membranes) and formation of membrane pores trigger subsequent biological responses, and the number and quality of pores are responsible for the cell fate. The immediate charging response of a biological cell to a nanosecond pulsed electric field exposure relies on the dielectric properties of its cellular components. Conversely, intense nanosecond pulses will change these properties due to conformational and functional changes. Hence, an understanding of biodielectric phenomena is necessary to explain the underlying interaction mechanisms between nanosecond pulses and biological materials. To this end, we have investigated the changes in dielectric characteristics of biological cells and tissues after exposure to multiple nanosecond pulses. Significant differences have been observed in dielectric properties and membrane integrity of Jurkat cells for exposures to nanosecond and microsecond pulsed electric fields despite delivery of the same energy, suggesting different pore formation and development mechanisms. The effect of nanosecond pulsed electric fields on the dielectric properties of Jurkat cells is long-lasting which is consistent with predictions of much longer pore resealing times for shorter pulses. Strong correlation between short-term plasma membrane conductivity and long-term cell survival has also been observed for different nanosecond-exposure conditions. Together with the studies on tissues, we demonstrate that dielectric spectroscopy is capable of assessing conformational and possibly functional changes of cells after exposure to nanosecond pulsed electric fields on biologically relevant time scales, and in turn, evaluate and compare the efficacy of chosen pulse parameters

MOLECULAR DYNAMIC SIMULATION OF ASIATIC ACID DERIVATIVES COMPLEX WITH INDUCIBLE NITRIC OXIDE SYNTHASE ENZYME AS AN ANTI-INFLAMMATORY

Objective: The aim of this study was to determine the stability interaction of asiatic acid derivatives (AA) complex with inducible nitric oxide synthase (iNOS) enzyme as an anti-inflammatory using Molecular Dynamic (MD) simulation. Methods: The methods were consisting of validation of molecular docking, molecular docking to calculate binding affinity within the complex between the compounds and iNOS enzyme by using MMGBSA (Molecular Mechanics/Generalized Born Surface Area), and MD system preparation, MD production as well as MD analysis using AMBER18. Results: The result of validation and molecular docking were AA5 has the most negative Gibbs energy that is -9.17 kcal/mol, which has better binding affinity than other derivatives than other derivatives. The molecular dynamics simulation of the modified structure of asiatic acid showed that binding energy value and RMSD of AA5, AA6 and AA9 have a lower value compared to arginine as a substrate of iNOS enzyme. Molecular Dynamics that have been occurred to the best three compounds chosen shown good result in terms of stability after 100 ns length simulation. And the lowest binding affinity has been achieved by a compound called AA5. Out of all ligands that have been simulated shown that their binding affinity was lower than AA5 that reached-44.6753 kcal/mol. Conclusion: This studies conclude that AA5 considerably more potential as a selective inhibitor of iNOS enzyme as an anti-inflammatory

New Monte Carlo Based Technique To Study DNA–Ligand Interactions

We present a new all-atom Monte Carlo technique capable of performing quick and accurate DNA–ligand conformational sampling. In particular, and using the PELE software as a frame, we have introduced an additional force field, an implicit solvent, and an anisotropic network model to effectively map the DNA energy landscape. With these additions, we successfully generated DNA conformations for a test set composed of six DNA fragments of A-DNA and B-DNA. Moreover, trajectories generated for cisplatin and its hydrolysis products identified the best interacting compound and binding site, producing analogous results to microsecond molecular dynamics simulations. Furthermore, a combination of the Monte Carlo trajectories with Markov State Models produced noncovalent binding free energies in good agreement with the published molecular dynamics results, at a significantly lower computational cost. Overall our approach will allow a quick but accurate sampling of DNA–ligand interactions.The authors thank the Barcelona Supercomputing Center for computational resources. This work was supported by grants from the European Research Council—2009-Adg25027-PELE European project and the Spanish Ministry of Economy and Competitiveness CTQ2013-48287 and “Juan de la Cierva” to F.L.Peer ReviewedPostprint (author's final draft

Folding@home: achievements from over twenty years of citizen science herald the exascale era

Simulations of biomolecules have enormous potential to inform our understanding of biology but require extremely demanding calculations. For over twenty years, the Folding@home distributed computing project has pioneered a massively parallel approach to biomolecular simulation, harnessing the resources of citizen scientists across the globe. Here, we summarize the scientific and technical advances this perspective has enabled. As the project's name implies, the early years of Folding@home focused on driving advances in our understanding of protein folding by developing statistical methods for capturing long-timescale processes and facilitating insight into complex dynamical processes. Success laid a foundation for broadening the scope of Folding@home to address other functionally relevant conformational changes, such as receptor signaling, enzyme dynamics, and ligand binding. Continued algorithmic advances, hardware developments such as GPU-based computing, and the growing scale of Folding@home have enabled the project to focus on new areas where massively parallel sampling can be impactful. While previous work sought to expand toward larger proteins with slower conformational changes, new work focuses on large-scale comparative studies of different protein sequences and chemical compounds to better understand biology and inform the development of small molecule drugs. Progress on these fronts enabled the community to pivot quickly in response to the COVID-19 pandemic, expanding to become the world's first exascale computer and deploying this massive resource to provide insight into the inner workings of the SARS-CoV-2 virus and aid the development of new antivirals. This success provides a glimpse of what's to come as exascale supercomputers come online, and Folding@home continues its work.Comment: 24 pages, 6 figure