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Article ; Online: Challenging issues in rheumatology: thoughts and perspectives.

Lim, Nathan / Wise, Leanna / Panush, Richard S

2021 Volume 40, Issue 5, Page(s) 1669–1672

MeSH term(s)	Humans ; Rheumatology
Language	English
Publishing date	2021-04-04
Publishing country	Germany
Document type	Editorial
ZDB-ID	604755-5
ISSN	1434-9949 ; 0770-3198
ISSN (online)	1434-9949
ISSN	0770-3198
DOI	10.1007/s10067-021-05709-4
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Article ; Online: Correction to: Challenging issues in rheumatology: thoughts and perspectives.

Lim, Nathan / Wise, Leanna / Panush, Richard S

Clinical rheumatology

2021 Volume 40, Issue 8, Page(s) 3389

Language	English
Publishing date	2021-06-15
Publishing country	Germany
Document type	Published Erratum
ZDB-ID	604755-5
ISSN	1434-9949 ; 0770-3198
ISSN (online)	1434-9949
ISSN	0770-3198
DOI	10.1007/s10067-021-05798-1
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Article ; Online: Fragment Pose Prediction Using Non-equilibrium Candidate Monte Carlo and Molecular Dynamics Simulations.

Lim, Nathan M / Osato, Meghan / Warren, Gregory L / Mobley, David L

Journal of chemical theory and computation

2020 Volume 16, Issue 4, Page(s) 2778–2794

Abstract: Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and how molecules bind, chemists can begin to build ideas on how to design improvements to increase binding affinities. In ... ...

Abstract	Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and how molecules bind, chemists can begin to build ideas on how to design improvements to increase binding affinities. In this retrospective study, we compare how computational approaches like docking, molecular dynamics (MD) simulations, and a non-equilibrium candidate Monte Carlo (NCMC)-based method (NCMC + MD) perform in predicting binding modes for a set of 12 fragment-like molecules, which bind to soluble epoxide hydrolase. We evaluate each method's effectiveness in identifying the dominant binding mode and finding additional binding modes (if any). Then, we compare our predicted binding modes to experimentally obtained X-ray crystal structures. We dock each of the 12 small molecules into the apo-protein crystal structure and then run simulations up to 1 μs each. Small and fragment-like molecules likely have smaller energy barriers separating different binding modes by virtue of relatively fewer and weaker interactions relative to drug-like molecules and thus likely undergo more rapid binding mode transitions. We expect, thus, to see more rapid transitions between binding modes in our study. Following this, we build Markov State Models to define our stable ligand binding modes. We investigate if adequate sampling of ligand binding modes and transitions between them can occur at the microsecond timescale using traditional MD or a hybrid NCMC+MD simulation approach. Our findings suggest that even with small fragment-like molecules, we fail to sample all the crystallographic binding modes using microsecond MD simulations, but using NCMC+MD, we have better success in sampling the crystal structure while obtaining the correct populations.
MeSH term(s)	Epoxide Hydrolases/chemistry ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Monte Carlo Method ; Protein Binding
Chemical Substances	Epoxide Hydrolases (EC 3.3.2.-)
Language	English
Publishing date	2020-03-27
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.9b01096
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics.

Sasmal, Sukanya / Gill, Samuel C / Lim, Nathan M / Mobley, David L

Journal of chemical theory and computation

2020 Volume 16, Issue 3, Page(s) 1854–1865

Abstract: Flexible ligands often have multiple binding modes or bound conformations that differ by rotation of a portion of the molecule around internal rotatable bonds. Knowledge of these binding modes is important for understanding the interactions stabilizing ... ...

Abstract	Flexible ligands often have multiple binding modes or bound conformations that differ by rotation of a portion of the molecule around internal rotatable bonds. Knowledge of these binding modes is important for understanding the interactions stabilizing the ligand in the binding pocket, and other studies indicate it is important for calculating accurate binding affinities. In this work, we use a hybrid molecular dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method to sample the different binding modes of several flexible ligands and also to estimate the population distribution of the modes. The NCMC move proposal is divided into three parts. The flexible part of the ligand is alchemically turned off by decreasing the electrostatics and steric interactions gradually, followed by rotating the rotatable bond by a random angle and then slowly turning the ligand back on to its fully interacting state. The alchemical steps prior to and after the move proposal help the surrounding protein and water atoms in the binding pocket relax around the proposed ligand conformation and increase move acceptance rates. The protein-ligand system is propagated using classical MD in between the NCMC proposals. Using this MD/NCMC method, we were able to correctly reproduce the different binding modes of inhibitors binding to two kinase targets-c-Jun N-terminal kinase-1 and cyclin-dependent kinase 2-at a much lower computational cost compared to conventional MD and umbrella sampling. This method is available as a part of the BLUES software package.
MeSH term(s)	Humans ; Ligands ; Molecular Dynamics Simulation/standards ; Monte Carlo Method
Chemical Substances	Ligands
Language	English
Publishing date	2020-02-24
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.9b01066
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Article ; Online: Enhancing Side Chain Rotamer Sampling Using Nonequilibrium Candidate Monte Carlo.

Burley, Kalistyn H / Gill, Samuel C / Lim, Nathan M / Mobley, David L

Journal of chemical theory and computation

2019 Volume 15, Issue 3, Page(s) 1848–1862

Abstract: Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such motions can be slow compared to simulation time scales, yet critical. Specifically, adequate sampling of side chain motions in protein binding ... ...

Abstract	Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such motions can be slow compared to simulation time scales, yet critical. Specifically, adequate sampling of side chain motions in protein binding pockets is crucial for obtaining accurate estimates of ligand binding free energies from molecular simulations. The time scale of side chain rotamer flips can range from a few ps to several hundred ns or longer, particularly in crowded environments like the interior of proteins. Here, we apply a mixed nonequilibrium candidate Monte Carlo (NCMC)/molecular dynamics (MD) method to enhance sampling of side chain rotamers. The NCMC portion of our method applies a switching protocol wherein the steric and electrostatic interactions between target side chain atoms and the surrounding environment are cycled off and then back on during the course of a move proposal. Between NCMC move proposals, simulation of the system continues via traditional molecular dynamics. Here, we first validate this approach on a simple, solvated valine-alanine dipeptide system and then apply it to a well-studied model ligand binding site in T4 lysozyme L99A. We compute the rate of rotamer transitions for a valine side chain using our approach and compare it to that of traditional molecular dynamics simulations. Here, we show that our NCMC/MD method substantially enhances side chain sampling, especially in systems where the torsional barrier to rotation is high (≥10 kcal/mol). These barriers can be intrinsic torsional barriers or steric barriers imposed by the environment. Overall, this may provide a promising strategy to selectively improve side chain sampling in molecular simulations.
Language	English
Publishing date	2019-02-11
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.8b01018
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Article: Improving the interfacial properties of CZTS photocathodes by Ag substitution

Tay, Ying Fan / Hadke, Shreyash Sudhakar / Zhang, Mengyuan / Lim, Nathan / Chiam, Sing Yang / Wong, Lydia Helena

Journal of materials chemistry A. 2020 May 12, v. 8, no. 18

2020

Abstract: Cu₂ZnSnS₄ (CZTS) is a promising photocathode in water splitting systems due to its appropriate conduction band position with the water reduction potential, suitable band gap and high absorption coefficient. However, CZTS has yet to demonstrate unbiased ... ...

Abstract	Cu₂ZnSnS₄ (CZTS) is a promising photocathode in water splitting systems due to its appropriate conduction band position with the water reduction potential, suitable band gap and high absorption coefficient. However, CZTS has yet to demonstrate unbiased solar to hydrogen efficiency above 1% in a photocathode–photoanode tandem setup unlike its CuInGaSe₂ chalcogenide counterpart due to its low onset potential and photocurrent. This low onset potential and photocurrent is believed to be due to the high density of defects in CZTS and at the CZTS/CdS interface which limits the open-circuit voltage in CZTS solar cells. In this work (AgₓCu₁₋ₓ)₂ZnSnS₄ (ACZTS) with Ag⁺ partially replacing Cu⁺ is fabricated by a solution process and investigated as a photocathode. Our ACZTS/CdS/Pt photocathode yields a maximum photocurrent of 17.7 mA cm⁻² at 0 VRHE with 4% Ag (x = 0.04) and a maximum onset potential of 0.85 VRHE with 8% Ag (x = 0.08), which is a substantial improvement from our CZTS/CdS/Pt photocathode that has a photocurrent of 13 mA cm⁻² and an onset potential of 0.65 VRHE. A combination of incident photon to current efficiency (IPCE) measurements done in a photoelectrochemical (PEC) and photovoltaic (PV) setup attributes the improvement to the interface properties. Other PV measurements such as capacitance–voltage profiling (CV) and Mott–Schottky measurements reveal a lower apparent carrier concentration and higher built-in voltage of ACZTS.
Keywords	absorbance ; cathodes ; copper zinc tin sulfide ; electric current ; electric potential difference ; hydrogen ; photons
Language	English
Dates of publication	2020-0512
Size	p. 8862-8867.
Publishing place	The Royal Society of Chemistry
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2702232-8
ISSN	2050-7496 ; 2050-7488
ISSN (online)	2050-7496
ISSN	2050-7488
DOI	10.1039/d0ta02042g
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Binding Modes and Metabolism of Caffeine.

Jandova, Zuzana / Gill, Samuel C / Lim, Nathan M / Mobley, David L / Oostenbrink, Chris

Chemical research in toxicology

2019 Volume 32, Issue 7, Page(s) 1374–1383

Abstract: A correct estimate of ligand binding modes and a ratio of their occupancies is crucial for calculations of binding free energies. The newly developed method BLUES combines molecular dynamics with nonequilibrium candidate Monte Carlo. Nonequilibrium ... ...

Abstract	A correct estimate of ligand binding modes and a ratio of their occupancies is crucial for calculations of binding free energies. The newly developed method BLUES combines molecular dynamics with nonequilibrium candidate Monte Carlo. Nonequilibrium candidate Monte Carlo generates a plethora of possible binding modes and molecular dynamics enables the system to relax. We used BLUES to investigate binding modes of caffeine in the active site of its metabolizing enzyme Cytochrome P450 1A2 with the aim of elucidating metabolite-formation profiles at different concentrations. Because the activation energies of all sites of metabolism do not show a clear preference for one metabolite over the others, the orientations in the active site must play a key role. In simulations with caffeine located in a spacious pocket above the I-helix, it points N3 and N1 to the heme iron, whereas in simulations where caffeine is in close proximity to the heme N7 and C8 are preferably oriented toward the heme iron. We propose a mechanism where at low caffeine concentrations caffeine binds to the upper part of the active site, leading to formation of the main metabolite paraxanthine. On the other hand, at high concentrations two molecules are located in the active site, forcing one molecule into close proximity to the heme and yielding metabolites theophylline and trimethyluretic acid. Our results offer an explanation of previously published experimental results.
MeSH term(s)	Caffeine/chemistry ; Caffeine/metabolism ; Catalytic Domain ; Cytochrome P-450 CYP1A2/chemistry ; Cytochrome P-450 CYP1A2/metabolism ; Heme/chemistry ; Humans ; Ligands ; Models, Chemical ; Molecular Dynamics Simulation ; Monte Carlo Method ; Protein Binding
Chemical Substances	Ligands ; Caffeine (3G6A5W338E) ; Heme (42VZT0U6YR) ; Cytochrome P-450 CYP1A2 (EC 1.14.14.1)
Language	English
Publishing date	2019-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.9b00030
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Zs.A 2320: Show issues

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Article ; Online: Characterization of JNJ-2482272 [4-(4-Methyl-2-(4-(Trifluoromethyl)Phenyl)Thiazole-5-yl) Pyrimidine-2-Amine] As a Strong Aryl Hydrocarbon Receptor Activator in Rat and Human.

Coe, Kevin J / Feinstein, Mark / Higgins, J William / Leung, Perry / Scott, Brian P / Skaptason, Judy / Tam, Yuen / Volak, Laurie P / Kinong, Jennifer / Bittner, Anton / McAllister, Heather / Lim, Nathan M / Hack, Michael / Koudriakova, Tatiana

Drug metabolism and disposition: the biological fate of chemicals

2022 Volume 50, Issue 8, Page(s) 1064–1076

Abstract: 4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure ... ...

Abstract	[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (C
MeSH term(s)	Amines ; Animals ; Cytochrome P-450 CYP1A1/metabolism ; Humans ; Pyrimidines/pharmacology ; Rats ; Receptors, Aryl Hydrocarbon/metabolism ; Thiazoles/pharmacology
Chemical Substances	Amines ; Pyrimidines ; Receptors, Aryl Hydrocarbon ; Thiazoles ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1)
Language	English
Publishing date	2022-06-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.121.000825
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Article ; Online: Enhancing water sampling of buried binding sites using nonequilibrium candidate Monte Carlo.

Bergazin, Teresa Danielle / Ben-Shalom, Ido Y / Lim, Nathan M / Gill, Sam C / Gilson, Michael K / Mobley, David L

Journal of computer-aided molecular design

2020 Volume 35, Issue 2, Page(s) 167–177

Abstract: Water molecules can be found interacting with the surface and within cavities in proteins. However, water exchange between bulk and buried hydration sites can be slow compared to simulation timescales, thus leading to the inefficient sampling of the ... ...

Abstract	Water molecules can be found interacting with the surface and within cavities in proteins. However, water exchange between bulk and buried hydration sites can be slow compared to simulation timescales, thus leading to the inefficient sampling of the locations of water. This can pose problems for free energy calculations for computer-aided drug design. Here, we apply a hybrid method that combines nonequilibrium candidate Monte Carlo (NCMC) simulations and molecular dynamics (MD) to enhance sampling of water in specific areas of a system, such as the binding site of a protein. Our approach uses NCMC to gradually remove interactions between a selected water molecule and its environment, then translates the water to a new region, before turning the interactions back on. This approach of gradual removal of interactions, followed by a move and then reintroduction of interactions, allows the environment to relax in response to the proposed water translation, improving acceptance of moves and thereby accelerating water exchange and sampling. We validate this approach on several test systems including the ligand-bound MUP-1 and HSP90 proteins with buried crystallographic waters removed. We show that our BLUES (NCMC/MD) method enhances water sampling relative to normal MD when applied to these systems. Thus, this approach provides a strategy to improve water sampling in molecular simulations which may be useful in practical applications in drug discovery and biomolecular design.
MeSH term(s)	Binding Sites ; Ligands ; Molecular Dynamics Simulation ; Monte Carlo Method ; Protein Binding ; Protein Conformation ; Proteins/chemistry ; Thermodynamics ; Water
Chemical Substances	Ligands ; Proteins ; Water (059QF0KO0R)
Language	English
Publishing date	2020-09-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	808166-9
ISSN	1573-4951 ; 0920-654X
ISSN (online)	1573-4951
ISSN	0920-654X
DOI	10.1007/s10822-020-00344-8
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Zs.A 2625: Show issues

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Article ; Online: Insights on small molecule binding to the Hv1 proton channel from free energy calculations with molecular dynamics simulations.

Lim, Victoria T / Geragotelis, Andrew D / Lim, Nathan M / Freites, J Alfredo / Tombola, Francesco / Mobley, David L / Tobias, Douglas J

Scientific reports

2020 Volume 10, Issue 1, Page(s) 13587

Abstract: Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. ... ...

Abstract	Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we computed relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We used alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model and shed light on the preferred tautomeric state of the channel blocker. This work lays the groundwork for future studies on adapting the blocker molecule for more effective inhibition of Hv1.
MeSH term(s)	Humans ; Ion Channel Gating/drug effects ; Ion Channel Gating/physiology ; Ion Channels/chemistry ; Ion Channels/metabolism ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Protein Conformation ; Protons ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Small Molecule Libraries/pharmacology ; Thermodynamics
Chemical Substances	HVCN1 protein, human ; Ion Channels ; Protons ; Small Molecule Libraries
Language	English
Publishing date	2020-08-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-70369-4
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