Umbrella sampling
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Gaussian accelerated molecular dynamics: Principles and applications Open
Gaussian accelerated molecular dynamics (GaMD) is a robust computational method for simultaneous unconstrained enhanced sampling and free energy calculations of biomolecules. It works by adding a harmonic boost potential to smooth biomolec…
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Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds Open
Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous sol…
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GENESIS 1.1: A hybrid‐parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms Open
GENeralized‐Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly paralleli…
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Smoothed Biasing Forces Yield Unbiased Free Energies with the Extended-System Adaptive Biasing Force Method Open
We report a theoretical description and numerical tests of the extended-system adaptive biasing force method (eABF), together with an unbiased estimator of the free energy surface from eABF dynamics. Whereas the original ABF approach uses …
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Exploring the aggregation free energy landscape of the amyloid-β protein (1–40) Open
Significance Protein aggregation and amyloid formation seem to be at the heart of the pathology of multiple neurodegenerative diseases, including Alzheimer’s disease. protein has long been considered one of the protein components that …
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Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding Open
Peptides mediate up to 40% of known protein–protein interactions in higher eukaryotes and play an important role in cellular signaling. However, it is challenging to simulate both binding and unbinding of peptides and calculate peptide bin…
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Demonstrating an Order-of-Magnitude Sampling Enhancement in Molecular Dynamics Simulations of Complex Protein Systems Open
Molecular dynamics (MD) simulations can describe protein motions in atomic detail, but transitions between protein conformational states sometimes take place on time scales that are infeasible or very expensive to reach by direct simulatio…
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Efficient Atomistic Simulation of Pathways and Calculation of Rate Constants for a Protein–Peptide Binding Process: Application to the MDM2 Protein and an Intrinsically Disordered p53 Peptide Open
The characterization of protein binding processes - with all of the key conformational changes - has been a grand challenge in the field of biophysics. Here, we have used the weighted ensemble path sampling strategy to orchestrate molecula…
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Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association Open
Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein-lipid and protein-protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with r…
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Flexible selection of the solute region in replica exchange with solute tempering: Application to protein-folding simulations Open
Replica-exchange molecular dynamics (REMD) and their variants have been widely used in simulations of the biomolecular structure and dynamics. Replica exchange with solute tempering (REST) is one of the methods where temperature of a pre-d…
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Streptavidin/biotin: Tethering geometry defines unbinding mechanics Open
Single-molecule force spectroscopy reveals how the mechanical stability of a widely used biomolecular complex varies fourfold.
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Surface force measurements and simulations of mussel-derived peptide adhesives on wet organic surfaces Open
Significance The need for bio-inspired wet adhesives has significantly increased in the past few decades (e.g., for dental and medical transplants, coronary artery coatings, cell encapsulants, etc.). However, the molecular basis behind cat…
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Characterizing the Diversity of the CDR-H3 Loop Conformational Ensembles in Relationship to Antibody Binding Properties Open
We present an approach to assess antibody CDR-H3 loops according to their dynamic properties using molecular dynamics simulations. We selected six antibodies in three pairs differing substantially in their individual promiscuity respective…
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Accurate Estimation of the Standard Binding Free Energy of Netropsin with DNA Open
DNA is the target of chemical compounds (drugs, pollutants, photosensitizers, etc.), which bind through non-covalent interactions. Depending on their structure and their chemical properties, DNA binders can associate to the minor or to the…
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Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules Open
Permeability (Pm) across biological membranes is of fundamental importance and a key factor in drug absorption, distribution, and development. Although the majority of drugs will be charged at some point during oral delivery, our understan…
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Exploring high dimensional free energy landscapes: Temperature accelerated sliced sampling Open
Biased sampling of collective variables is widely used to accelerate rare events in molecular simulations and to explore free energy surfaces. However, computational efficiency of these methods decreases with increasing number of collectiv…
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Large-Scale Membrane Permeability Prediction of Cyclic Peptides Crossing a Lipid Bilayer Based on Enhanced Sampling Molecular Dynamics Simulations Open
Membrane permeability is a significant obstacle facing the development of cyclic peptide drugs. However, membrane permeation mechanisms are poorly understood. To investigate common features of permeable (and nonpermeable) designs, it is ne…
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Effect of Ca2+ on the promiscuous target-protein binding of calmodulin Open
Calmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling pathways. CaM has the ability to bind more than 300 different target peptides in a …
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Computational methods for exploring protein conformations Open
Proteins are dynamic molecules that can transition between a potentially wide range of structures comprising their conformational ensemble. The nature of these conformations and their relative probabilities are described by a high-dimensio…
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Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques Open
In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–prote…
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Comparing Solvophobic and Multivalent Induced Collapse in Polyelectrolyte Brushes Open
Coarse-grained molecular dynamics enhanced by free-energy sampling methods is used to examine the roles of solvophobicity and multivalent salts on polyelectrolyte brush collapse. Specifically, we demonstrate that while ostensibly similar, …
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Free energy analysis and mechanism of base pair stacking in nicked DNA Open
The equilibrium of stacked and unstacked base pairs is of central importance for all nucleic acid structure formation processes. The stacking equilibrium is influenced by intramolecular interactions between nucleosides but also by interact…
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Fundamental Insights into Proton-Coupled Electron Transfer in Soybean Lipoxygenase from Quantum Mechanical/Molecular Mechanical Free Energy Simulations Open
The proton-coupled electron transfer (PCET) reaction catalyzed by soybean lipoxygenase has served as a prototype for understanding hydrogen tunneling in enzymes. Herein this PCET reaction is studied with mixed quantum mechanical/molecular …
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Rare behavior of growth processes via umbrella sampling of trajectories Open
We compute probability distributions of trajectory observables for reversible and irreversible growth processes. These results reveal a correspondence between reversible and irreversible processes, at particular points in parameter space, …
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Simulating Protein Mediated Hydrolysis of ATP and Other Nucleoside Triphosphates by Combining QM/MM Molecular Dynamics with Advances in Metadynamics Open
The protein mediated hydrolysis of nucleoside triphosphates such as ATP or GTP is one of the most important and challenging biochemical reactions in nature. The chemical environment (water structure, catalytic metal, and amino acid residue…
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Calcium Phosphate Prenucleation Complexes in Water by Means of ab Initio Molecular Dynamics Simulations Open
The nucleation of calcium phosphates, the main inorganic component of bone and tooth tissues, is thought to proceed by aggregation of prenucleation clusters recently identified as calcium triphosphate complexes. We have performed ab initio…
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Enhanced Monte Carlo Methods for Modeling Proteins Including Computation of Absolute Free Energies of Binding Open
The generation of a complete ensemble of geometrical configurations is required to obtain reliable estimations of absolute binding free energies by alchemical free energy methods. Molecular dynamics (MD) is the most popular sampling method…
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Selecting Collective Variables and Free-Energy Methods for Peptide Translocation across Membranes Open
The selective permeability of cellular membranes is a crucial property for controlled transport into and out of cells. Molecules that can bypass the cellular machinery and spontaneously translocate across membranes could be used as therape…
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The combined force field-sampling problem in simulations of disordered amyloid-β peptides Open
Molecular dynamics simulations of intrinsically disordered proteins (IDPs) can provide high resolution structural ensembles if the force field is accurate enough and if the simulation sufficiently samples the conformational space of the ID…
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Free Energy Calculations of Membrane Permeation: Challenges Due to Strong Headgroup–Solute Interactions Open
Understanding how different classes of molecules move across biological membranes is a prerequisite to predicting a solute's permeation rate, which is a critical factor in the fields of drug design and pharmacology. We use biased molecular…