scholarly journals Adaptive Biasing Combined with Hamiltonian Replica Exchange to Improve Umbrella Sampling Free Energy Simulations

2014 ◽  
Vol 106 (2) ◽  
pp. 404a-405a
Author(s):  
Fabian T. Zeller
Keyword(s):  
Free Energy ◽  
Umbrella Sampling ◽  
Replica Exchange ◽  
Hamiltonian Replica Exchange ◽  
Adaptive Biasing ◽  
Energy Simulations

Finite-temperature effects in enzymatic reactions — Insights from QM/MM free-energy simulations

2009 ◽  
Vol 87 (10) ◽  
pp. 1322-1337 ◽  
Author(s):  
Hans Martin Senn ◽  
Johannes Kästner ◽  
Jürgen Breidung ◽  
Walter Thiel
Keyword(s):  
Free Energy ◽  
Finite Temperature ◽  
Temperature Effects ◽  
Density Functional ◽  
Umbrella Sampling ◽  
Chorismate Mutase ◽  
Enzymatic Reactions ◽  
Energy Data ◽  
Energy Simulations ◽  
Entropic Contribution

We report potential-energy and free-energy data for three enzymatic reactions: carbon–halogen bond formation in fluorinase, hydrogen abstraction from camphor in cytochrome P450cam, and chorismate-to-prephenate Claisen rearrangement in chorismate mutase. The results were obtained by combined quantum mechanics/molecular mechanics (QM/MM) optimizations and two types of QM/MM free-energy simulations (free-energy perturbation and umbrella sampling) using semi-empirical or density-functional QM methods. Based on these results and our previously published free-energy data on electrophilic substitution in para-hydroxybenzoate hydroxylase, we discuss the importance of finite-temperature effects in the chemical step of enzyme reactions. We find that the entropic contribution to the activation barrier is generally rather small, usually of the order of 5 kJ mol–1 or less, consistent with the notion that enzymes bind and pre-organize the reactants in the active site. A somewhat larger entropic contribution is encountered in the case of chorismate mutase where the pericyclic transition state is intrinsically more rigid than the chorismate reactant (also in the enzyme). The present results suggest that barriers from QM/MM geometry optimization may often be close to free-energy barriers for the chemical step in enzymatic reactions.

Displacement of carbonates in Ca2UO2(CO3)3 by amidoxime-based ligands from free-energy simulations

2018 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Bo Li ◽  
Chad Priest ◽  
De-en Jiang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Umbrella Sampling ◽  
Nacl Solution ◽  
Classical Molecular Dynamics ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Free Energy Profiles

Classical molecular dynamics simulations coupled with umbrella sampling reveal the atomistic processes and free-energy profiles of the displacement of carbonate groups in the Ca2UO2(CO3)3 complex by amidoxime-based ligands in a 0.5 M NaCl solution.

scholarly journals A replica exchange umbrella sampling (REUS) approach to predict host–guest binding free energies in SAMPL8 challenge

2021 ◽  
Author(s):  
Mahdi Ghorbani ◽  
Phillip S. Hudson ◽  
Michael R. Jones ◽  
Félix Aviat ◽  
Rubén Meana-Pañeda ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Free Energy Calculations ◽  
Replica Exchange ◽  
Free Energies ◽  
Guest Binding ◽  
Binding Free Energy Calculations ◽  
Force Field Parameters ◽  
Binding Free Energies

AbstractIn this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host–guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 $${\text{kcal}}/{\text{mol}}$$ kcal / mol from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of $$2.65$$ 2.65 and $$1.72 {\text{kcal}}/{\text{mol}}$$ 1.72 kcal / mol , respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2019 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Water Solution ◽  
Energy Difference ◽  
Umbrella Sampling ◽  
Energy Stability ◽  
Functional Protein ◽  
Relative Free Energy ◽  
Energy Simulations ◽  
Experimental Findings

The Human Immunodeficiency Virus Type 1 nucleocapsid 7 (NCp7) is a multi-functional protein formed by N-terminal and C-terminal domains surrounding two Zn-fingers, linked by a stretch of basic residues, which play a key role in the viral replication. We report the first NCp7 polarizable molecular dynamics (MD) study using the AMOEBA force field complemented by non-polarizable CHARMM simulations. Specifically, we compared the relative free-energy stability of two extreme conformations: a compact one having two aromatic residues from each finger, partially stacked, denoted A; and an unfolded one, with the two residues apart, denoted B. Each of these conformations had been previously experimentally advocated to prevail in solution. We compared their theoretical relative free-energy stability using accelerated MD sampling techniques (Steered MD and Umbrella Sampling) and showed that there was a low free energy difference between them. As A and B do not differ in stability by more than 1-1.5 kcal/mol, they should thus coexist in water solution reconciling earlier NMR experimental findings.

scholarly journals Capturing the Flexibility of a Protein-Ligand Complex: Binding Free Energies from Different Enhanced Sampling Techniques

2020 ◽  
Author(s):  
Sebastian Wingbermühle ◽  
Lars V. Schäfer
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Replica Exchange ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Ligand Complex ◽  
Mhc I ◽  
Partial Dissociation

Enhanced sampling techniques are a promising approach to obtain reliable binding free energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*35:01 to systematically investigate the performance of Umbrella Sampling (US), Replica Exchange with Solute Tempering 2 (REST2), Bias Exchange Umbrella Sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered Metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can handle best the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free energy minimum in the pMHC I under study. These findings might be relevant also for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.<br>

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