Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations?
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 isome...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/14/4426 |
| _version_ | 1797444876006064128 |
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| author | Piero Procacci |
| author_facet | Piero Procacci |
| author_sort | Piero Procacci |
| collection | DOAJ |
| description | 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-hopping simulation by the addition of a “hot-zone” scaling factor to the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-stratification (FEP<sup>+</sup> approach), provided that the additive hot-zone scaling factors are tuned and optimized using preliminary ordinary replica-exchange simulation of the end-states. |
| first_indexed | 2024-03-09T13:18:48Z |
| format | Article |
| id | doaj.art-bd99bbc5248d46748528694eb98bc0e6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T13:18:48Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-bd99bbc5248d46748528694eb98bc0e62023-11-30T21:33:15ZengMDPI AGMolecules1420-30492022-07-012714442610.3390/molecules27144426Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations?Piero Procacci0Chemistry Department, University of Florence, Via Lastruccia n.3, I-50019 Sesto Firentino, ItalyIn 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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-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 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-hopping simulation by the addition of a “hot-zone” scaling factor to the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-stratification (FEP<sup>+</sup> approach), provided that the additive hot-zone scaling factors are tuned and optimized using preliminary ordinary replica-exchange simulation of the end-states.https://www.mdpi.com/1420-3049/27/14/4426drug designmolecular dynamicsbinding free energyreplica exchangeFEPFEP<sup>+</sup> |
| spellingShingle | Piero Procacci Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations? Molecules drug design molecular dynamics binding free energy replica exchange FEP FEP<sup>+</sup> |
| title | Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations? |
| title_full | Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations? |
| title_fullStr | Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations? |
| title_full_unstemmed | Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations? |
| title_short | Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations? |
| title_sort | does hamiltonian replica exchange via lambda hopping enhance the sampling in alchemical free energy calculations |
| topic | drug design molecular dynamics binding free energy replica exchange FEP FEP<sup>+</sup> |
| url | https://www.mdpi.com/1420-3049/27/14/4426 |
| work_keys_str_mv | AT pieroprocacci doeshamiltonianreplicaexchangevialambdahoppingenhancethesamplinginalchemicalfreeenergycalculations |