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Van der Spoel, DavidORCID iD iconorcid.org/0000-0002-7659-8526
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Publications (10 of 129) Show all publications
Hosseini, A. N. & van der Spoel, D. (2024). Martini on the Rocks: Can a Coarse-Grained Force Field Model Crystals?. Journal of Physical Chemistry Letters, 15(4), 1079-1088
Open this publication in new window or tab >>Martini on the Rocks: Can a Coarse-Grained Force Field Model Crystals?
2024 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 15, no 4, p. 1079-1088Article in journal (Refereed) Published
Abstract [en]

Computational chemistry is an important tool in numerous scientific disciplines, including drug discovery and structural biology. Coarse-grained models offer simple representations of molecular systems that enable simulations of large-scale systems. Because there has been an increase in the adoption of such models for simulations of biomolecular systems, critical evaluation is warranted. Here, the stability of the amyloid peptide and organic crystals is evaluated using the Martini 3 coarse-grained force field. The crystals change shape drastically during the simulations. Radial distribution functions show that the distance between backbone beads in β-sheets increases by ∼1 Å, breaking the crystals. The melting points of organic compounds are much too low in the Martini force field. This suggests that Martini 3 lacks the specific interactions needed to accurately simulate peptides or organic crystals without imposing artificial restraints. The problems may be exacerbated by the use of the 12-6 potential, suggesting that a softer potential could improve this model for crystal simulations.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-523723 (URN)10.1021/acs.jpclett.4c00012 (DOI)001156033900001 ()38261634 (PubMedID)
Funder
Swedish Research Council, 2020-05059Swedish Research Council, 2022-06725Uppsala UniversityeSSENCE - An eScience CollaborationNational Academic Infrastructure for Supercomputing in Sweden (NAISS)National Supercomputer Centre (NSC), Sweden
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-27Bibliographically approved
Lüking, M., Van der Spoel, D., Elf, J. & Tribello, G. A. A. (2023). Can molecular dynamics be used to simulate biomolecular recognition?. Journal of Chemical Physics, 158(18), Article ID 184106.
Open this publication in new window or tab >>Can molecular dynamics be used to simulate biomolecular recognition?
2023 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 158, no 18, article id 184106Article in journal (Refereed) Published
Abstract [en]

There are many problems in biochemistry that are difficult to study experimentally. Simulation methods are appealing due to direct availability of atomic coordinates as a function of time. However, direct molecular simulations are challenged by the size of systems and the time scales needed to describe relevant motions. In theory, enhanced sampling algorithms can help to overcome some of the limitations of molecular simulations. Here, we discuss a problem in biochemistry that offers a significant challenge for enhanced sampling methods and that could, therefore, serve as a benchmark for comparing approaches that use machine learning to find suitable collective variables. In particular, we study the transitions LacI undergoes upon moving between being non-specifically and specifically bound to DNA. Many degrees of freedom change during this transition and that the transition does not occur reversibly in simulations if only a subset of these degrees of freedom are biased. We also explain why this problem is so important to biologists and the transformative impact that a simulation of it would have on the understanding of DNA regulation.

Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2023
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-504051 (URN)10.1063/5.0146899 (DOI)000985389300007 ()37158325 (PubMedID)
Funder
Swedish Research Council, 2016.06213Swedish Research Council, 2018-05973Knut and Alice Wallenberg Foundation, 2018-05973Swedish National Infrastructure for Computing (SNIC), 2016.0077Swedish National Infrastructure for Computing (SNIC), SNIC 2021/3-8Swedish National Infrastructure for Computing (SNIC), SNIC 2022/3-26Swedish National Infrastructure for Computing (SNIC), SNIC 2021/6-268Swedish National Infrastructure for Computing (SNIC), SNIC 2022/6-261Swedish National Infrastructure for Computing (SNIC), SNIC 2022/23-373Swedish National Infrastructure for Computing (SNIC), SNIC 2021/6-294Swedish National Infrastructure for Computing (SNIC), 2022/6-344
Available from: 2023-06-09 Created: 2023-06-09 Last updated: 2023-08-23Bibliographically approved
Schmidt, L., Van der Spoel, D. & Walz, M.-M. (2023). Probing Phase Transitions in Organic Crystals Using Atomistic MD Simulations. ACS PHYSICAL CHEMISTRY AU, 3(1), 84-93
Open this publication in new window or tab >>Probing Phase Transitions in Organic Crystals Using Atomistic MD Simulations
2023 (English)In: ACS PHYSICAL CHEMISTRY AU, ISSN 2694-2445, Vol. 3, no 1, p. 84-93Article in journal (Refereed) Published
Abstract [en]

A profound understanding of the physicochemical properties of organic crystals is crucial for topics from material science to drug discovery. Using molecular dynamics (MD) simulations with a sufficiently accurate force field, microscopic insight into structure and dynamics can be obtained of materials, including liquids and biomolecules. They are a valuable complement to experimental investigations that are used routinely in drug design, but not very often for studies of organic crystals. Indeed, the often delicate interactions in organic crystals act as a sensitive probe to investigate the accuracy of force fields. Here, we study the structural, dynamic, and thermodynamic properties of 30 organic crystals using the popular general AMBER force field (GAFF). In particular, we investigate both solid-solid and solid-liquid phase transitions. Melting points were determined using extensive solid-liquid coexistence simulations. For many compounds, we detect a phase transition from an ordered to a plastic crystal in the simulations. Based on the translational and rotational dynamics of the compounds, we can rationalize the properties of the plastic crystal phase. MD simulations can therefore help to answer the important question of whether or not organic crystals have a plastic crystal phase, and if so, what are the underlying factors in the molecular structure determining that.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
Keywords
organic crystals, phase, transitions, molecular, dynamics simulation, melting points, plastic crystals, benchmark, polymorphism
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-511118 (URN)10.1021/acsphyschemau.2c00045 (DOI)001047158700001 ()
Funder
Swedish Research Council, 2020-05059Swedish Research Council, SNIC2020-3-8Swedish Research Council, SNIC2021-3-8
Available from: 2023-09-13 Created: 2023-09-13 Last updated: 2023-09-13Bibliographically approved
Hosseini, A. N. & Van der Spoel, D. (2023). Simulations of Amyloid-Forming Peptides in the Crystal State. The Protein Journal, 42(3), 192-204
Open this publication in new window or tab >>Simulations of Amyloid-Forming Peptides in the Crystal State
2023 (English)In: The Protein Journal, ISSN 1572-3887, E-ISSN 1875-8355, Vol. 42, no 3, p. 192-204Article in journal (Refereed) Published
Abstract [en]

There still is little treatment available for amyloid diseases, despite their significant impact on individuals and the social and economic implications for society. One reason for this is that the physical nature of amyloid formation is not understood sufficiently well. Therefore, fundamental research at the molecular level remains necessary to support the development of therapeutics. A few structures of short peptides from amyloid-forming proteins have been determined. These can in principle be used as scaffolds for designing aggregation inhibitors. Attempts to this end have often used the tools of computational chemistry, in particular molecular simulation. However, few simulation studies of these peptides in the crystal state have been presented so far. Hence, to validate the capability of common force fields (AMBER19SB, CHARMM36m, and OPLS-AA/M) to yield insight into the dynamics and structural stability of amyloid peptide aggregates, we have performed molecular dynamics simulations of twelve different peptide crystals at two different temperatures. From the simulations, we evaluate the hydrogen bonding patterns, the isotropic B-factors, the change in energy, the Ramachandran plots, and the unit cell parameters and compare the results with the crystal structures. Most crystals are stable in the simulations but for all force fields there is at least one that deviates from the experimental crystal, suggesting more work is needed on these models.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Crystal structure, Amyloid fibril, Molecular dynamic simulation, Standard force fields
National Category
Physical Chemistry Biophysics Theoretical Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-511071 (URN)10.1007/s10930-023-10119-3 (DOI)000982379700001 ()37145206 (PubMedID)
Available from: 2023-09-07 Created: 2023-09-07 Last updated: 2023-09-07Bibliographically approved
Balint, M., Zsido, B. Z., Van der Spoel, D. & Hetenyi, C. (2022). Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design. International Journal of Molecular Sciences, 23(13), Article ID 7313.
Open this publication in new window or tab >>Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 13, article id 7313Article in journal (Refereed) Published
Abstract [en]

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
ligand, mechanism, pathway, dynamics, channel
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-481378 (URN)10.3390/ijms23137313 (DOI)000822317100001 ()35806314 (PubMedID)
Available from: 2022-08-11 Created: 2022-08-11 Last updated: 2022-08-11Bibliographically approved
Van der Spoel, D., Zhang, J. & Zhang, H. (2022). Quantitative predictions from molecular simulations using explicit or implicit interactions. Wiley Interdisciplinary Reviews. Computational Molecular Science, 12(1), Article ID e1560.
Open this publication in new window or tab >>Quantitative predictions from molecular simulations using explicit or implicit interactions
2022 (English)In: Wiley Interdisciplinary Reviews. Computational Molecular Science, ISSN 1759-0876, E-ISSN 1759-0884, Vol. 12, no 1, article id e1560Article, review/survey (Refereed) Published
Abstract [en]

Equilibrium simulations of molecular systems allow to extract many physicochemical properties. Given an "accurate enough" model, a "large enough" simulation system and "long enough" simulations, such calculations should yield accurate predictions of properties that can be tested by experimental measurements. Non-equilibrium simulations can be used as a tool to obtain specific properties like viscosity or conductivity, but they have the drawback that in general only one property per simulation is produced. In addition, a range of methods is available for computing free energy differences. We here review the state of the art of using classical simulation models for generating quantitative predictions. Popular force fields have significant predictive power already but there is room for improvement. Bonded force potentials may need to be replaced by more accurate ones to better reproduce vibrational frequencies. Simplification of non-bonded force terms, such as cut-offs for electrostatic or dispersion interactions, should be avoided. Routine usage of force field methods will therefore require some tuning of parameters. Despite the extensive toolbox that is available for producing quantitative results, the computational cost of explicit solvent simulation is significant and therefore, approximate methods like implicit solvent models remain popular and are still being developed. Based on fundamental arguments as well as on examples of solvation free energies, host-guest complexation and non-covalent association of molecules in solution, we conclude that implicit solvents as well as algorithmic simplifications are most useful when validation using experimental data or rigorous theoretical treatments is possible.

Place, publisher, year, edition, pages
John Wiley & SonsWiley, 2022
Keywords
infrared spectroscopy, Lennard-Jones PME, water, beta-cyclodextrin
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-470258 (URN)10.1002/wcms.1560 (DOI)000664216500001 ()
Funder
Swedish Research Council, 2020-05059
Available from: 2022-03-23 Created: 2022-03-23 Last updated: 2024-01-15Bibliographically approved
Gapsys, V., Yildirim, A., Aldeghi, M., Khalak, Y., Van der Spoel, D. & de Groot, B. L. (2021). Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches. Communications Chemistry, 4, Article ID 61.
Open this publication in new window or tab >>Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches
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2021 (English)In: Communications Chemistry, E-ISSN 2399-3669, Vol. 4, article id 61Article in journal (Refereed) Published
Abstract [en]

Molecular dynamics-based approaches to calculate absolute protein-ligand binding free energy often rely on equilibrium free energy perturbation (FEP) protocols. Here, the authors study ligands binding to bromodomains and T4 lysozyme and find that both equilibrium and non-equilibrium approaches converge to the same results with the non-equilibrium method converging faster than FEP. The accurate calculation of the binding free energy for arbitrary ligand-protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein-ligand binding affinity.

Place, publisher, year, edition, pages
Springer NatureNATURE RESEARCH, 2021
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-445579 (URN)10.1038/s42004-021-00498-y (DOI)000656226900004 ()
Funder
Swedish Research Council, 2013-5947Swedish National Infrastructure for Computing (SNIC), SNIC2017-12-41EU, Horizon 2020, H2020-INFRAEDI-02-2018-823830
Available from: 2021-07-16 Created: 2021-07-16 Last updated: 2024-01-15Bibliographically approved
Brooks, C. L. ., Case, D. A., Plimpton, S., Roux, B., Van der Spoel, D. & Tajkhorshid, E. (2021). Classical molecular dynamics. Journal of Chemical Physics, 154(10), Article ID 100401.
Open this publication in new window or tab >>Classical molecular dynamics
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2021 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 154, no 10, article id 100401Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
American Institute of Physics (AIP)AIP Publishing, 2021
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-440923 (URN)10.1063/5.0045455 (DOI)000628803300001 ()33722022 (PubMedID)
Available from: 2021-04-22 Created: 2021-04-22 Last updated: 2024-01-15Bibliographically approved
Shehu, A. & Van der Spoel, D. (2021). Editorial overview: Theory and simulation and their new friends. Current opinion in structural biology, 67, III-V
Open this publication in new window or tab >>Editorial overview: Theory and simulation and their new friends
2021 (English)In: Current opinion in structural biology, ISSN 0959-440X, E-ISSN 1879-033X, Vol. 67, p. III-VArticle in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
CURRENT BIOLOGY LTD, 2021
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-443368 (URN)10.1016/j.sbi.2021.02.003 (DOI)000647703900001 ()33707064 (PubMedID)
Available from: 2021-05-28 Created: 2021-05-28 Last updated: 2021-05-28Bibliographically approved
Walz, M.-M. & Van der Spoel, D. (2021). Microscopic origins of conductivity in molten salts unraveled by computer simulations. Communications Chemistry, 4, Article ID 9.
Open this publication in new window or tab >>Microscopic origins of conductivity in molten salts unraveled by computer simulations
2021 (English)In: Communications Chemistry, E-ISSN 2399-3669, Vol. 4, article id 9Article in journal (Refereed) Published
Abstract [en]

Molten salts are crucial materials in energy applications, such as batteries, thermal energy storage systems or concentrated solar power plants. Still, the determination and interpretation of basic physico-chemical properties like ionic conductivity, mobilities and transference numbers cause debate. Here, we explore a method for determination of ionic electrical mobilities based on non-equilibrium computer simulations. Partial conductivities are then determined as a function of system composition and temperature from simulations of molten LiF alpha Cl beta I gamma (with alpha + beta + gamma = 1). High conductivity does not necessarily coincide with high Li+ mobility for molten LiF alpha Cl beta I gamma systems at a given temperature. In salt mixtures, the lighter anions on average drift along with Li+ towards the negative electrode when applying an electric field and only the heavier anions move towards the positive electrode. In conclusion, the microscopic origin of conductivity in molten salts is unraveled here based on accurate ionic electrical mobilities and an analysis of the local structure and kinetics of the materials. Molten salt electrolytes are widely used in energy storage and conversion, but our understanding of conductivity trends remains incomplete. Here, computational approaches are used to determine ionic electrical mobilities, local structures, and kinetics, unravelling the origins of conductivity in molten lithium halide salts.

Place, publisher, year, edition, pages
Springer NatureNATURE RESEARCH, 2021
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-435900 (URN)10.1038/s42004-020-00446-2 (DOI)000612378000001 ()
Available from: 2021-03-08 Created: 2021-03-08 Last updated: 2024-01-15Bibliographically approved
Projects
Modelling of ionic liquids for applications in green chemistry [2009-07761_VR]; Uppsala UniversitySpecies Specific Insecticides Against the Malaria Mosquito and the Migratory Locust [2009-06502_VR]; Uppsala UniversityNext Generation Molecular Simulations [2013-05947_VR]; Uppsala UniversityQuantitative Molecular Simulation [2020-05059_VR]; Uppsala University; Publications
Hosseini, A. N. & van der Spoel, D. (2024). Martini on the Rocks: Can a Coarse-Grained Force Field Model Crystals?. Journal of Physical Chemistry Letters, 15(4), 1079-1088
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7659-8526

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