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  1. Article ; Online: Dealing with Induced Fit, Conformational Selection, and Secondary Poses in Molecular Dynamics Simulations for Reliable Free Energy Predictions.

    Procacci, Piero

    Journal of chemical theory and computation

    2023  Volume 19, Issue 23, Page(s) 8942–8954

    Abstract: In this study, we have tested the performance of standard molecular dynamics (MD) simulations, replicates of shorter standard MD simulations, and Hamiltonian Replica Exchange (HREM) simulations for the sampling of two macrocyclic hosts for guest delivery, ...

    Abstract In this study, we have tested the performance of standard molecular dynamics (MD) simulations, replicates of shorter standard MD simulations, and Hamiltonian Replica Exchange (HREM) simulations for the sampling of two macrocyclic hosts for guest delivery, characterized by induced fit (phenyl-based host) and conformation selection (naphthyl-based host) and of the ODR-BRD4(I) drug-receptor system where the ligand can assume two main poses. For the optimization of the HREM simulation, we have proposed and tested an on-the-fly iterative scheme for equalizing the acceptance ratio along the replica progression at a constant replica number resulting in a moderate impact of the sampling efficiency. Concerning standard MD, we have found that, while splitting the total allocated simulation time in short MD replicates can reproduce the sampling efficiency of HREM in the phenyl-based host and in the ODR-BRD4(I) complex, in the naphthyl-based macrocycle, characterized by long-lived metastable states, enhanced sampling techniques are the only viable alternative for a reliable canonical sampling of the rugged conformational landscape.
    Language English
    Publishing date 2023-12-01
    Publishing country United States
    Document type Journal Article
    ISSN 1549-9626
    ISSN (online) 1549-9626
    DOI 10.1021/acs.jctc.3c00867
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations?

    Procacci, Piero

    Molecules (Basel, Switzerland)

    2022  Volume 27, Issue 14

    Abstract: In the context of computational drug design, we examine the effectiveness of the enhanced sampling techniques in state-of-the-art free energy calculations based on alchemical molecular dynamics simulations. In a paradigmatic molecule with competition ... ...

    Abstract In the context of computational drug design, we examine the effectiveness of the enhanced sampling techniques in state-of-the-art free energy calculations based on alchemical molecular dynamics simulations. In a paradigmatic molecule with competition between conformationally restrained E and Z isomers whose probability ratio is strongly affected by the coupling with the environment, we compare the so-called λ-hopping technique to the Hamiltonian replica exchange methods assessing their convergence behavior as a function of the enhanced sampling protocols (number of replicas, scaling factors, simulation times). We found that the pure λ-hopping, commonly used in solvation and binding free energy calculations via alchemical free energy perturbation techniques, is ineffective in enhancing the sampling of the isomeric states, exhibiting a pathological dependence on the initial conditions. Correct sampling can be restored in λ-hopping simulation by the addition of a "hot-zone" scaling factor to the λ-stratification (FEP
    MeSH term(s) Entropy ; Molecular Dynamics Simulation ; Thermodynamics
    Language English
    Publishing date 2022-07-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules27144426
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  3. Article ; Online: Relative Binding Free Energy between Chemically Distant Compounds Using a Bidirectional Nonequilibrium Approach.

    Procacci, Piero

    Journal of chemical theory and computation

    2022  Volume 18, Issue 6, Page(s) 4014–4026

    Abstract: In the context of advanced hit-to-lead drug design based on atomistic molecular dynamics simulations, we propose a dual topology alchemical approach for calculating the relative binding free energy (RBFE) between two chemically distant compounds. The ... ...

    Abstract In the context of advanced hit-to-lead drug design based on atomistic molecular dynamics simulations, we propose a dual topology alchemical approach for calculating the relative binding free energy (RBFE) between two chemically distant compounds. The method (termed NE-RBFE) relies on the enhanced sampling of the end-states in bulk and in the bound state via Hamiltonian Replica Exchange, alchemically connected by a series of independent and fast nonequilibrium (NE) simulations. The technique has been implemented in a bidirectional fashion, applying the Crooks theorem to the NE work distributions for RBFE predictions. The dissipation of the NE process, negatively affecting accuracy, has been minimized by introducing a smooth regularization based on shifted electrostatic and Lennard-Jones non bonded potentials. As a challenging testbed, we have applied our method to the calculation of the RBFEs in the recent host-guest SAMPL international contest, featuring a macrocyclic host with guests varying in the net charge, volume, and chemical fingerprints. Closure validation has been successfully verified in cycles involving compounds with disparate Tanimoto coefficients, volume, and net charge. NE-RBFE is specifically tailored for massively parallel facilities and can be used with little or no code modification on most of the popular software packages supporting nonequilibrium alchemical simulations, such as Gromacs, Amber, NAMD, or OpenMM. The proposed methodology bypasses most of the entanglements and limitations of the standard single topology RBFE approach for strictly congeneric series based on free-energy perturbation, such as slowly relaxing cavity water, sampling issues along the alchemical stratification, and the need for highly overlapping molecular fingerprints.
    MeSH term(s) Entropy ; Ligands ; Molecular Dynamics Simulation ; Static Electricity ; Thermodynamics
    Chemical Substances Ligands
    Language English
    Publishing date 2022-06-01
    Publishing country United States
    Document type Journal Article
    ISSN 1549-9626
    ISSN (online) 1549-9626
    DOI 10.1021/acs.jctc.2c00295
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  4. Article ; Online: Methodological uncertainties in drug-receptor binding free energy predictions based on classical molecular dynamics.

    Procacci, Piero

    Current opinion in structural biology

    2020  Volume 67, Page(s) 127–134

    Abstract: Computational approaches are becoming an essential tool in modern drug design and discovery, with fast compound triaging using a combination of machine learning and docking techniques followed by molecular dynamics binding free energies assessment using ... ...

    Abstract Computational approaches are becoming an essential tool in modern drug design and discovery, with fast compound triaging using a combination of machine learning and docking techniques followed by molecular dynamics binding free energies assessment using alchemical techniques. The traditional MD-based alchemical free energy perturbation (FEP) method faces severe sampling issues that may limits its reliability in automated workflows. Here we review the major sources of uncertainty in FEP protocols for drug discovery, showing how the sampling problem can be effectively tackled by switching to nonequilibrium alchemical techniques.
    MeSH term(s) Ligands ; Molecular Dynamics Simulation ; Pharmaceutical Preparations ; Protein Binding ; Receptors, Drug ; Reproducibility of Results ; Thermodynamics ; Uncertainty
    Chemical Substances Ligands ; Pharmaceutical Preparations ; Receptors, Drug
    Language English
    Publishing date 2020-11-18
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1068353-7
    ISSN 1879-033X ; 0959-440X
    ISSN (online) 1879-033X
    ISSN 0959-440X
    DOI 10.1016/j.sbi.2020.08.001
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    Zs.A 3206: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  5. Article ; Online: A remark on the efficiency of the double-system/single-box nonequilibrium approach in the SAMPL6 SAMPLing challenge.

    Procacci, Piero

    Journal of computer-aided molecular design

    2020  Volume 34, Issue 6, Page(s) 635–639

    Abstract: The alchemical nonequilibrium switching technique was one of several methods in the top tier of performance in the recent SAMPL6 SAMPLing challenge in both accuracy and efficiency. In this paper, in the context of nonequilibrium alchemical switching, we ... ...

    Abstract The alchemical nonequilibrium switching technique was one of several methods in the top tier of performance in the recent SAMPL6 SAMPLing challenge in both accuracy and efficiency. In this paper, in the context of nonequilibrium alchemical switching, we compare the efficiency of the double-system/single-box (DSSB) approach (used in the SAMPL6 challenges) to the standard single-system/double-box method (SSDB). Exploiting the Crooks theorem in a simple but effective test case, we analytically show that the DSSB approach is almost twice as efficient as SSDB for slow near-equilibrium switching but it gives basically no gain over the conventional SSDB approach when the variance of the work distribution exceeds few [Formula: see text], with the potential of producing artifacts and entanglements if not judiciously implemented.
    MeSH term(s) Bridged-Ring Compounds/chemistry ; Imidazoles/chemistry ; Ligands ; Molecular Dynamics Simulation ; Protein Binding ; Thermodynamics
    Chemical Substances Bridged-Ring Compounds ; Imidazoles ; Ligands
    Language English
    Publishing date 2020-04-11
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 808166-9
    ISSN 1573-4951 ; 0920-654X
    ISSN (online) 1573-4951
    ISSN 0920-654X
    DOI 10.1007/s10822-020-00312-2
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    Zs.A 2625: Show issues Location:
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  6. Article ; Online: Comment on "Statistical efficiency of methods for computing free energy of hydration" [J. Chem. Phys. 149, 144111 (2018)].

    Procacci, Piero

    The Journal of chemical physics

    2019  Volume 150, Issue 12, Page(s) 127101

    Language English
    Publishing date 2019-03-25
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 3113-6
    ISSN 1089-7690 ; 0021-9606
    ISSN (online) 1089-7690
    ISSN 0021-9606
    DOI 10.1063/1.5086743
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  7. Article ; Online: Identification of Potential Inhibitors of the SARS-CoV-2 NSP13 Helicase via Structure-Based Ligand Design, Molecular Docking and Nonequilibrium Alchemical Simulations.

    Di Paco, Giorgio / Macchiagodena, Marina / Procacci, Piero

    ChemMedChem

    2024  , Page(s) e202400095

    Abstract: We have assembled a computational pipeline based on virtual screening, docking techniques, and nonequilibrium molecular dynamics simulations, with the goal of identifying possible inhibitors of the SARS-CoV-2 NSP13 helicase, catalyzing by ATP hydrolysis ... ...

    Abstract We have assembled a computational pipeline based on virtual screening, docking techniques, and nonequilibrium molecular dynamics simulations, with the goal of identifying possible inhibitors of the SARS-CoV-2 NSP13 helicase, catalyzing by ATP hydrolysis the unwinding of double or single-stranded RNA in the viral replication process inside the host cell. The druggable sites for broad-spectrum inhibitors are represented by the RNA binding sites at the 5' entrance and 3' exit of the central channel, a structural motif that is highly conserved across coronaviruses. Potential binders were first generated using structure-based ligand techniques. Their potency was estimated by using four popular docking scoring functions. Common docking hits for NSP13 were finally tested using advanced nonequilibrium alchemical techniques for binding free energy calculations on a high-performing parallel cluster. Four potential NSP13 inhibitors with potency from submicrimolar to nanomolar were finally identified.
    Language English
    Publishing date 2024-03-08
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202400095
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    Zs.A 6280: Show issues Location:
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  8. Article ; Online: Precision and computational efficiency of nonequilibrium alchemical methods for computing free energies of solvation. II. Unidirectional estimates.

    Procacci, Piero

    The Journal of chemical physics

    2019  Volume 151, Issue 14, Page(s) 144115

    Abstract: ... molecules in the context of molecular dynamics simulations. In Paper I [Procacci, J. Chem. Phys. 151, 144113 ...

    Abstract The present paper is the second part of a series of papers aimed at assessing the accuracy of alchemical computational approaches based on nonequilibrium techniques for solvation free energy of organic molecules in the context of molecular dynamics simulations. In Paper I [Procacci, J. Chem. Phys. 151, 144113 (2019)], we dealt with bidirectional estimates of solvation free energies using nonequilibrium approaches. Here, we assess accuracy and precision of unidirectional estimates with the focus on the Gaussian and Jarzynski estimators. We present a very simple methodology to increase the statistics in the work distribution, hence boosting the accuracy and precision of the Jarzynski unidirectional estimates at no extra cost, exploiting the observed decorrelation between the random variables represented by the Lennard-Jones solute-solvent recoupling or decoupling work and by the electrostatic work due to the charging/discharging of the solute in the solvent.
    Language English
    Publishing date 2019-10-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3113-6
    ISSN 1089-7690 ; 0021-9606
    ISSN (online) 1089-7690
    ISSN 0021-9606
    DOI 10.1063/1.5120616
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  9. Article ; Online: Accuracy, precision, and efficiency of nonequilibrium alchemical methods for computing free energies of solvation. I. Bidirectional approaches.

    Procacci, Piero

    The Journal of chemical physics

    2019  Volume 151, Issue 14, Page(s) 144113

    Abstract: In the context of molecular dynamics simulations, alchemical approaches based on nonequilibrium techniques are recently emerging as a powerful method for the computation of solvation free energy of druglike compounds. Here, we present a rigorous and ... ...

    Abstract In the context of molecular dynamics simulations, alchemical approaches based on nonequilibrium techniques are recently emerging as a powerful method for the computation of solvation free energy of druglike compounds. Here, we present a rigorous and extensive analysis of the accuracy and precision of the method as a function of the parameters qualifying the nonequilibrium alchemical protocol (e.g., number and length of the nonequilibrium trajectories and decoupling or recoupling alchemical schedule) on a selection of drug-size organic compounds characterized by a nontrivial conformational free energy landscape. The study is organized in two contributions. The first paper includes a detailed description of method and of the conformational behavior of molecular systems. Results are focused on the accuracy and precision bidirectional estimates of solvation free energy, notably those based on the so-called Bennett acceptance ratio. In the second paper, unidirectional estimates for solvation free energy are analyzed in depth.
    Language English
    Publishing date 2019-10-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3113-6
    ISSN 1089-7690 ; 0021-9606
    ISSN (online) 1089-7690
    ISSN 0021-9606
    DOI 10.1063/1.5120615
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  10. Article ; Online: Solvation free energies via alchemical simulations: let's get honest about sampling, once more.

    Procacci, Piero

    Physical chemistry chemical physics : PCCP

    2019  Volume 21, Issue 25, Page(s) 13826–13834

    Abstract: Free energy perturbation (FEP) approaches with stratification have seen widespread and increasing use in computational studies of biologically relevant molecules. However, when the molecular systems are characterized by a complex conformational free ... ...

    Abstract Free energy perturbation (FEP) approaches with stratification have seen widespread and increasing use in computational studies of biologically relevant molecules. However, when the molecular systems are characterized by a complex conformational free energy landscape, the assessment of convergence remains a concern for many practitioners. The sampling problem in FEP has been authoritatively addressed in a recent perspective paper [D. Mobley, J. Comput.-Aided Mol. Des., 2012, 26, 93], incisively entitled "Let's get honest about sampling". Here, I return to the issue of sampling in the determination of the octanol-water partition coefficient for a synthetic precursor of kinase inhibitors that has been included in the recent extension of the SAMPL6 blind challenge of log P coefficients. I will show that even for this simple compound, whose conformational space is essentially dictated by two sp
    MeSH term(s) Models, Molecular ; Molecular Conformation ; Octanols/chemistry ; Protein Kinase Inhibitors/chemistry ; Quinazolines/chemistry ; Solvents/chemistry ; Thermodynamics ; Uncertainty ; Water/chemistry
    Chemical Substances Octanols ; Protein Kinase Inhibitors ; Quinazolines ; Solvents ; Water (059QF0KO0R)
    Language English
    Publishing date 2019-06-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 1476244-4
    ISSN 1463-9084 ; 1463-9076
    ISSN (online) 1463-9084
    ISSN 1463-9076
    DOI 10.1039/c9cp02808k
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