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):  
Binding Free Energy ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Replica Exchange ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Ligand Complex ◽  
Mhc I ◽  
Flexible Protein ◽  
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 systematic strengths and weaknesses of the four enhanced sampling techniques used, demonstrating that BEUS can handle best the enthalpic and entropic sampling challenges posed by the system. We expect these findings to be relevant also for other flexible protein-ligand complexes with competing enthalpically and entropically stabilized minima.<br>

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>

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>

Capturing the Flexibility of a Protein-Ligand Complex with Enhanced Sampling Techniques: Binding Free Energies from Umbrella Sampling, REST2, and Bias Exchange

2019 ◽  
Author(s):  
Sebastian Wingbermühle ◽  
Lars V. Schäfer
Keyword(s):  
Degrees Of Freedom ◽  
Large Scale ◽  
Statistical Error ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Ligand Complex ◽  
Mhc I ◽  
Binding Groove

The performance of the three popular enhanced sampling techniques Umbrella Sampling (US), Replica Exchange with Solute Tempering 2 (REST2), and Bias Exchange (BE) is tested on Major Histocompatibility Complex I (MHC I) binding an antigenic peptide. The configurational flexibility of peptide-MHC I complexes (pMHC I) is key to their immunological function and must therefore be captured thoroughly by the sampling techniques used to yield accurate thermodynamics of pMHC I. Here, we calculate the Potential of Mean Force (PMF) for the dissociation of the peptide N-terminus from the MHC I binding groove. We carefully analyze the statistical error of the resulting PMF and the sampling of the orthogonal degrees of freedom to assess how well the three sampling techniques used can handle large-scale configurational flexibility.<br>

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

2019 ◽  
Author(s):  
Joshua Horton ◽  
Alice Allen ◽  
Daniel Cole
Keyword(s):  
Quantum Mechanics ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Quantum Mechanical ◽  
Enhanced Sampling ◽  
Relative Binding ◽  
Stringent Test ◽  
Flexible Protein ◽  
P38α Map Kinase

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

scholarly journals Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

2017 ◽  
Author(s):  
Irfan Alibay ◽  
Kepa K. Burusco ◽  
Neil J. Bruce ◽  
Richard A. Bryce
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Biological Action ◽  
Sialyl Lewis X ◽  
Enhanced Sampling ◽  
Sialyl Lewis ◽  
Aqueous Solvent ◽  
A Minor

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the <sup>4</sup>C<sub>1</sub> form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p>

scholarly journals Exploring Protocols to Build Reservoirs to Accelerate Replica Exchange MD Simulations

2020 ◽  
Author(s):  
koushik kasavajhala ◽  
kenneth lam ◽  
Carlos Simmerling
Keyword(s):  
Amino Acids ◽  
Sampling Method ◽  
Convergence Rates ◽  
Md Simulations ◽  
Replica Exchange ◽  
Conformational Sampling ◽  
Enhanced Sampling ◽  
Replica Exchange Molecular Dynamics ◽  
The Past ◽  
Biomolecular Simulations

Replica Exchange Molecular Dynamics (REMD) is a widely used enhanced sampling method for accelerating biomolecular simulations. During the past two decades, several variants of REMD have been developed to further improve the rate of conformational sampling of REMD. One such variant, Reservoir REMD (RREMD), was shown to improve the rate of conformational sampling by around 5-20x. Despite the significant increase in sampling speed, RREMD methods have not been widely used due to the difficulties in building the reservoir and also due to the code not being available on the GPUs.<br><br>In this work, we ported the AMBER RREMD code onto GPUs making it 20x faster than the CPU code. Then, we explored protocols for building Boltzmann-weighted reservoirs as well as non-Boltzmann reservoirs, and tested how each choice affects the accuracy of the resulting RREMD simulations. We show that, using the recommended protocols outlined here, RREMD simulations can accurately reproduce Boltzmann-weighted ensembles obtained by much more expensive conventional REMD simulations, with at least 15x faster convergence rates even for larger proteins (>50 amino acids) compared to conventional REMD.

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.

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