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Article ; Online: Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases.

Champion, Candide / Gall, René / Ries, Benjamin / Rieder, Salomé R / Barros, Emilia P / Riniker, Sereina

Journal of chemical information and modeling

2023 Volume 63, Issue 22, Page(s) 7133–7147

Abstract: Alchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of ... ...

Abstract	Alchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of pairwise free-energy methods to rank potential binders from best to worst is impacted by the combinatorial increase in calculations to perform when the number of molecules to assess grows. To address this fundamental limitation, our group has developed replica-exchange enveloping distribution sampling (RE-EDS), a pathway-independent multistate method, enabling the calculation of alchemical free-energy differences between multiple ligands (
MeSH term(s)	Thermodynamics ; Entropy ; Molecular Dynamics Simulation ; Protein Binding ; Ligands
Chemical Substances	Ligands
Language	English
Publishing date	2023-11-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c01469
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Article ; Online: Accounting for Solvation Correlation Effects on the Thermodynamics of Water Networks in Protein Cavities.

Barros, Emilia P / Ries, Benjamin / Champion, Candide / Rieder, Salomé R / Riniker, Sereina

Journal of chemical information and modeling

2023 Volume 63, Issue 6, Page(s) 1794–1805

Abstract: Macromolecular recognition and ligand binding are at the core of biological function and drug discovery efforts. Water molecules play a significant role in mediating the protein-ligand interaction, acting as more than just the surrounding medium by ... ...

Abstract	Macromolecular recognition and ligand binding are at the core of biological function and drug discovery efforts. Water molecules play a significant role in mediating the protein-ligand interaction, acting as more than just the surrounding medium by affecting the thermodynamics and thus the outcome of the binding process. As individual water contributions are impossible to measure experimentally, a range of computational methods have emerged to identify hydration sites in protein pockets and characterize their energetic contributions for drug discovery applications. Even though several methods model solvation effects explicitly, they focus on determining the stability of specific water sites independently and neglect solvation correlation effects upon replacement of clusters of water molecules, which typically happens in hit-to-lead optimization. In this work, we rigorously determine the conjoint effects of replacing all combinations of water molecules in protein binding pockets through the use of the RE-EDS multistate free-energy method, which combines Hamiltonian replica exchange (RE) and enveloping distribution sampling (EDS). Applications on the small bovine pancreatic trypsin inhibitor and four proteins of the bromodomain family illustrate the extent of solvation correlation effects on water thermodynamics, with the favorability of replacement of the water sites by pharmacophore probes highly dependent on the composition of the water network and the pocket environment. Given the ubiquity of water networks in biologically relevant protein targets, we believe our approach can be helpful for computer-aided drug discovery by providing a pocket-specific and
MeSH term(s)	Animals ; Cattle ; Water/chemistry ; Ligands ; Proteins/chemistry ; Thermodynamics ; Protein Binding
Chemical Substances	Water (059QF0KO0R) ; Ligands ; Proteins
Language	English
Publishing date	2023-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.2c01610
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Article ; Online: Frame Shifts Affect the Stability of Collagen Triple Helices.

Fiala, Tomas / Barros, Emilia P / Ebert, Marc-Olivier / Ruijsenaars, Enrico / Riniker, Sereina / Wennemers, Helma

Journal of the American Chemical Society

2022 Volume 144, Issue 40, Page(s) 18642–18649

Abstract: Collagen model peptides (CMPs), composed of proline-( ... ...

Abstract	Collagen model peptides (CMPs), composed of proline-(2
MeSH term(s)	Amino Acid Sequence ; Circular Dichroism ; Collagen/chemistry ; Glycine ; Hydroxyproline/chemistry ; Peptides/chemistry ; Proline/chemistry
Chemical Substances	Peptides ; Collagen (9007-34-5) ; Proline (9DLQ4CIU6V) ; Hydroxyproline (RMB44WO89X) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2022-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c08727
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Article ; Online: On the Interpretation of subtilisin Carlsberg Time-Resolved Fluorescence Anisotropy Decays: Modeling with Classical Simulations.

Lopez, Alvaro J / Barros, Emília P / Martínez, Leandro

Journal of chemical information and modeling

2019 Volume 60, Issue 2, Page(s) 747–755

Abstract: In this work, we discuss the challenging time-resolved fluorescence anisotropy of subtilisin Carlsberg (SC), which contains a single Trp residue and is a model fluorescence system. Experimental decay rates and quenching data suggest that the fluorophore ... ...

Abstract	In this work, we discuss the challenging time-resolved fluorescence anisotropy of subtilisin Carlsberg (SC), which contains a single Trp residue and is a model fluorescence system. Experimental decay rates and quenching data suggest that the fluorophore should be exposed to water, but the Trp is partially buried in a hydrophobic pocket in the crystallographic structure. In order to study this inconsistency, molecular dynamics simulations were performed to predict the anisotropy decay rates and emission wavelengths of the Trp. We confirmed the inconsistency of the crystallographic structure with the experimentally observed fluorescence data and performed free energy calculations to show that the buried Trp conformation is 2 orders of magnitude (∼3 kcal/mol) more stable than the solvent-exposed one. However, molecular dynamics simulations in which the Trp side chain was restricted to solvent-exposed conformations displayed a maximum Trp emission wavelength shifted toward lower energies and decay rates compatible with the experimentally probed rates. Therefore, if the solvent-exposed conformations are the most important emitters, the experimental anisotropy can be compatibilized with the crystallographic structure. The most likely explanation is that the fluorescence of the most probable conformation in solution, observed in the crystal, is quenched, and this is consistent with the low quantum yield of Trp113 of SC. Additionally, some experiments might have probed denatured or lysed SC structures. SC anisotropy provides an interesting target for the study of fluorescence anisotropy using simulations, which can be used to test and exemplify how modeling can aid the interpretation of experimental data in a system where structure and solution experiments appear to be inconsistent.
MeSH term(s)	Fluorescence Polarization ; Models, Molecular ; Protein Conformation ; Solvents/chemistry ; Subtilisins/chemistry ; Thermodynamics
Chemical Substances	Solvents ; Subtilisins (EC 3.4.21.-)
Language	English
Publishing date	2019-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.9b00539
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Article ; Online: Predicting Collagen Triple Helix Stability through Additive Effects of Terminal Residues and Caps.

Fiala, Tomas / Barros, Emilia P / Heeb, Rahel / Riniker, Sereina / Wennemers, Helma

Angewandte Chemie (International ed. in English)

2022 Volume 62, Issue 3, Page(s) e202214728

Abstract: Collagen model peptides (CMPs) consisting of proline-(2S,4R)-hydroxyproline-glycine (POG) repeats have provided a breadth of knowledge of the triple helical structure of collagen, the most abundant protein in mammals. Predictive tools for triple helix ... ...

Abstract	Collagen model peptides (CMPs) consisting of proline-(2S,4R)-hydroxyproline-glycine (POG) repeats have provided a breadth of knowledge of the triple helical structure of collagen, the most abundant protein in mammals. Predictive tools for triple helix stability have, however, lagged behind since the effect of CMPs with different frames ([POG]
MeSH term(s)	Animals ; Collagen/chemistry ; Peptides/chemistry ; Proline/chemistry ; Hydroxyproline/chemistry ; Glycine ; Mammals
Chemical Substances	Collagen (9007-34-5) ; Peptides ; Proline (9DLQ4CIU6V) ; Hydroxyproline (RMB44WO89X) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2022-12-14
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202214728
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Article: Replica-Exchange Enveloping Distribution Sampling: Calculation of Relative Free Energies in GROMOS.

Rieder, Salomé R / Ries, Benjamin / Champion, Candide / Barros, Emilia P / Hünenberger, Philippe H / Riniker, Sereina

Chimia

2022 Volume 76, Issue 4, Page(s) 327–330

Abstract: Molecular dynamics (MD) simulations have become an important tool to investigate biological systems. Free-energy calculations based on MD are playing an increasingly important role for computer-aided drug design and material discovery in recent years. ... ...

Abstract	Molecular dynamics (MD) simulations have become an important tool to investigate biological systems. Free-energy calculations based on MD are playing an increasingly important role for computer-aided drug design and material discovery in recent years. Free-energy differences between pairs of end-states can be estimated using well-established methods such as thermodynamic integration (TI) or Bennett's acceptance ratio (BAR). An attractive alternative is the recently developed replica-exchange enveloping distribution sampling (RE-EDS) method, which enables estimating relative free-energy differences between multiple molecules from a single simulation. Here, we provide an introduction to the principles underlying RE-EDS and give an overview of the RE-EDS pipeline. In addition, we provide a description of the two complementary tools RestraintMaker and amber2gromos. We briefly discuss the findings of three recent applications of RE-EDS to calculate relative binding or hydration free energies. In all three studies, good agreement was found between the results obtained using RE-EDS and experimental values as well as values obtained using other free-energy methods.
Language	English
Publishing date	2022-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1516-7
ISSN	0009-4293
ISSN	0009-4293
DOI	10.2533/chimia.2022.327
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Article ; Online: Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure.

Ries, Benjamin / Normak, Karl / Weiß, R Gregor / Rieder, Salomé / Barros, Emília P / Champion, Candide / König, Gerhard / Riniker, Sereina

Journal of computer-aided molecular design

2022 Volume 36, Issue 2, Page(s) 117–130

Abstract: The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free- ... ...

Abstract	The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free-energy difference between pairs of ligands. Thus, the comparison of multiple ligands requires the construction of a "state graph", in which the compounds are connected by alchemical transformations. The computational cost can be optimized by reducing the state graph to a minimal set of transformations. However, this may require individual adaptation of the sampling strategy if a transformation process does not converge in a given simulation time. In contrast, path-free methods like replica-exchange enveloping distribution sampling (RE-EDS) allow the sampling of multiple states within a single simulation without the pre-definition of alchemical transition paths. To optimize sampling and convergence, a set of RE-EDS parameters needs to be estimated in a pre-processing step. Here, we present an automated procedure for this step that determines all required parameters, improving the robustness and ease of use of the methodology. To illustrate the performance, the relative binding free energies are calculated for a series of checkpoint kinase 1 inhibitors containing challenging transformations in ring size, opening/closing, and extension, which reflect changes observed in scaffold hopping. The simulation of such transformations with RE-EDS can be conducted with conventional force fields and, in particular, without soft bond-stretching terms.
MeSH term(s)	Entropy ; Ligands ; Molecular Dynamics Simulation ; Thermodynamics
Chemical Substances	Ligands
Language	English
Publishing date	2022-01-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	808166-9
ISSN	1573-4951 ; 0920-654X
ISSN (online)	1573-4951
ISSN	0920-654X
DOI	10.1007/s10822-021-00436-z
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Article ; Online: Recent developments in multiscale free energy simulations.

Barros, Emilia P / Ries, Benjamin / Böselt, Lennard / Champion, Candide / Riniker, Sereina

Current opinion in structural biology

2021 Volume 72, Page(s) 55–62

Abstract: Physics-based free energy simulations enable the rigorous calculation of properties, such as conformational equilibria, solvation or binding free energies. While historically most applications have occurred at the atomistic level of resolution, a range ... ...

Abstract	Physics-based free energy simulations enable the rigorous calculation of properties, such as conformational equilibria, solvation or binding free energies. While historically most applications have occurred at the atomistic level of resolution, a range of advances in the past years make it possible now to reliably cross the temporal, spatial and theory scales for the modeling of complex systems or the efficient prediction of results at the accuracy level of expensive quantum-mechanical calculations. In this mini-review, we discuss recent methodological advances as well as opportunities opened up by the introduction of machine learning approaches, which tackle the diverse challenges across the different scales, improve the accuracy and feasibility, and push the boundaries of multiscale free energy simulations.
MeSH term(s)	Entropy ; Machine Learning ; Thermodynamics
Language	English
Publishing date	2021-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2021.08.003
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Article ; Online: An integrated view of p53 dynamics, function, and reactivation.

Demir, Özlem / Barros, Emilia P / Offutt, Tavina L / Rosenfeld, Mia / Amaro, Rommie E

Current opinion in structural biology

2021 Volume 67, Page(s) 187–194

Abstract: The tumor suppressor p53 plays a vital role in responding to cell stressors such as DNA damage, hypoxia, and tumor formation by inducing cell-cycle arrest, senescence, or apoptosis. Expression level alterations and mutational frequency implicates p53 in ... ...

Abstract	The tumor suppressor p53 plays a vital role in responding to cell stressors such as DNA damage, hypoxia, and tumor formation by inducing cell-cycle arrest, senescence, or apoptosis. Expression level alterations and mutational frequency implicates p53 in most human cancers. In this review, we show how both computational and experimental methods have been used to provide an integrated view of p53 dynamics, function, and reactivation potential. We argue that p53 serves as an exceptional case study for developing methods in modeling intrinsically disordered proteins. We describe how these methods can be leveraged to improve p53 reactivation molecule design and other novel therapeutic modalities, such as PROteolysis TARgeting Chimeras (PROTACs).
MeSH term(s)	Apoptosis ; Computational Biology ; DNA Damage ; Humans ; Neoplasms/genetics ; Proteolysis ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2021-01-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2020.11.005
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Article ; Online: Replica-Exchange Enveloping Distribution Sampling Using Generalized AMBER Force-Field Topologies: Application to Relative Hydration Free-Energy Calculations for Large Sets of Molecules.

Rieder, Salomé R / Ries, Benjamin / Schaller, Kay / Champion, Candide / Barros, Emilia P / Hünenberger, Philippe H / Riniker, Sereina

Journal of chemical information and modeling

2022 Volume 62, Issue 12, Page(s) 3043–3056

Abstract: Free-energy differences between pairs of end-states can be estimated based on molecular dynamics (MD) simulations using standard pathway-dependent methods such as thermodynamic integration (TI), free-energy perturbation, or Bennett's acceptance ratio. ... ...

Abstract	Free-energy differences between pairs of end-states can be estimated based on molecular dynamics (MD) simulations using standard pathway-dependent methods such as thermodynamic integration (TI), free-energy perturbation, or Bennett's acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS), on the other hand, allows for the sampling of multiple end-states in a single simulation without the specification of any pathways. In this work, we use the RE-EDS method as implemented in GROMOS together with generalized AMBER force-field (GAFF) topologies, converted to a GROMOS-compatible format with a newly developed GROMOS++ program
MeSH term(s)	Molecular Dynamics Simulation ; Thermodynamics ; Water
Chemical Substances	Water (059QF0KO0R)
Language	English
Publishing date	2022-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.2c00383
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