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Simple Entropy Terms for End-Point Binding Free Energy Calculations
Title
Simple Entropy Terms for End-Point Binding Free Energy Calculations
Creator
Menzer, William Michael
Date
2019
Description
We introduce a number of computationally inexpensive modifications to the MM/PBSA and MM/GBSA estimators for binding free energies, which are...
Show moreWe introduce a number of computationally inexpensive modifications to the MM/PBSA and MM/GBSA estimators for binding free energies, which are based on average receptor−ligand interaction energies in simulations of a noncovalent complex, to improve the treatment of entropy: second- and higher-order terms in a cumulant expansion and a confining potential on ligand external degrees of freedom. We also consider a filter for snapshots where ligands have drifted from the initial binding pose. The variations were tested on six sets of systems for which binding modes and free energies have previously been experimentally determined. For some data sets, none of the tested estimators led to results significantly correlated with measured free energies. In data sets with nontrivial correlation, a ligand RMSD cutoff of 3 Å and a second-order truncation of the cumulant expansion was found to be comparable or better than the average interaction energy by several statistical metrics.
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Efficiency of Stratification for Ensemble Reduction based on docking scores
Title
Efficiency of Stratification for Ensemble Reduction based on docking scores
Creator
Zhang, Hexi
Date
2018
Description
Molecular docking has been widely used in structure-based drug design to virtually screen large chemical libraries to predict the prefer...
Show moreMolecular docking has been widely used in structure-based drug design to virtually screen large chemical libraries to predict the prefer conformations ligands that could bind the target site. Protein flexibility is a major issue that could be solved by ensemble docking which is docking to ‘ensemble’ of protein rigid conformations, such as snapshots obtained by molecular dynamics simulations. Our group has developed a method called ‘Efficiency of Stratification’ to evaluate a number of common snapshot selection strategies using a quality metric from stratified sampling (Xie et al. [19]). Docking was performed to four proteins and with each ligand numbers sets of up to five hundred ligands. In this paper, we generated distance matrices based on docking score to analysis the performance of the efficiency of stratification method. We observed that most docking score based score-based distance matrices have had better performance than structure-based distance matrices and with including any structure-based component overwhelms the docking-score component. Only a few ligands are required to get a good distance matrix.
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SEPARATING NOBLE GASES SUCH AS KRYPTON AND XENON FROM NUCLEAR POWER PLANTS OFF-GAS USING DD3R ZEOLITIC MEMBRANES: A COMPUTATIONAL MOLECULAR DYNAMICS STUDY
Title
SEPARATING NOBLE GASES SUCH AS KRYPTON AND XENON FROM NUCLEAR POWER PLANTS OFF-GAS USING DD3R ZEOLITIC MEMBRANES: A COMPUTATIONAL MOLECULAR DYNAMICS STUDY
Creator
BASHMMAKH, BANDAR JAMAL S.
Date
2021
Description
Noble gas fission products generated within nuclear power reactors, such as Kr and Xe, are currently discharged into the atmosphere. This...
Show moreNoble gas fission products generated within nuclear power reactors, such as Kr and Xe, are currently discharged into the atmosphere. This practice has a major economic drawback because of the high value associated with some of these gases. Zeolites, nanoporous materials suitable for gas separation processes, have become of major interest due to the potentially high selectivity for such separations. We have used nonequilibrium molecular dynamics to investigate the separation performance of DD3R framework zeolitic membranes (using LAMMPS software package) for such separations. Our studies have shown that the DD3R membrane shows promise for high selectivity ratios of Kr over Xe. The effects of pressure, temperature and pure vs. mixture gas feed conditions are studied in this work to understand at the molecular level the mechanisms of these (Kr/Xe) separations. MD runs show an agreement with most experimental trends in the permeation of Kr/Xe pure and mixed gases using DD3R zeolite with high separation factor, despite the absence of Xe complete permeation through the membrane because of MD timescale limitation, signaling much slower diffusion in comparison to Kr which is a desired trend in looking for high separation factors.
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Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Title
Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator
Kaczmarek, Julia A.
Date
2023
Description
The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
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