scholarly journals Towards Convergence in Folding Simulations of RNA Tetraloops: Comparison of Enhanced Sampling Techniques and Effects of Force Field Corrections

2021 ◽  
Author(s):  
Vojtech Mlynsky ◽  
Michal Janecek ◽  
Petra Kuhrova ◽  
Thorben Frohlking ◽  
Michal Otyepka ◽  
...  
Keyword(s):  
Time Scale ◽  
Md Simulations ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Native State ◽  
Good Convergence ◽  
Empirical Potentials ◽  
Folding Simulations ◽  
Established Technique

Atomistic molecular dynamics (MD) simulations represent established technique for investigation of RNA structural dynamics. Despite continuous development, contemporary RNA simulations still suffer from suboptimal accuracy of empirical potentials (force fields, ffs) and sampling limitations. Development of efficient enhanced sampling techniques is important for two reasons. First, they allow to overcome the sampling limitations and, second, they can be used to quantify ff imbalances provided they reach a sufficient convergence. Here, we study two RNA tetraloops (TLs), namely the GAGA and UUCG motifs. We perform extensive folding simulations and calculate folding free energies (ΔGfold) with the aim to compare different enhanced sampling techniques and to test several modifications of the nonbonded terms extending the AMBER OL3 RNA ff. We demonstrate that replica exchange solute tempering (REST2) simulations with 12-16 replicas do not show any sign of convergence even when extended to time scale of 120 μs per replica. However, combination of REST2 with well-tempered metadynamics (ST-MetaD) achieves good convergence on a time-scale of 5-10 μs per replica, improving the sampling efficiency by at least two orders of magnitude. Effects of ff modifications on ΔGfold energies were initially explored by the reweighting approach and then validated by new simulations. We tested several manually-prepared variants of gHBfix potential which improve stability of the native state of both TLs by up to ~2 kcal/mol. This is sufficient to conveniently stabilize the folded GAGA TL while the UUCG TL still remains under-stabilized. Appropriate adjustment of van der Waals parameters for C-H...O5' base-phosphate interaction are also shown to be capable of further stabilizing the native states of both TLs by ~0.6 kcal/mol.

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 Combining Machine Learning and Enhanced Sampling Techniques for Efficient and Accurate Calculation of Absolute Binding Free Energies

2020 ◽  
Vol 16 (7) ◽  
pp. 4641-4654 ◽  
Author(s):  
Rhys Evans ◽  
Ladislav Hovan ◽  
Gareth A. Tribello ◽  
Benjamin P. Cossins ◽  
Carolina Estarellas ◽  
...  
Keyword(s):  
Machine Learning ◽  
Sampling Techniques ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Accurate Calculation ◽  
Binding Free Energies

scholarly journals Thermodynamics and free energy landscape of BAR-domain dimerization from molecular simulations

2020 ◽  
Author(s):  
Adip Jhaveri ◽  
Dhruw Maisuria ◽  
Matthew Varga ◽  
Dariush Mohammadyani ◽  
Margaret E Johnson
Keyword(s):  
Free Energy ◽  
Energy Surface ◽  
Md Simulations ◽  
Coarse Grained ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Free Energy Surface ◽  
Bar Domain ◽  
Bar Domains ◽  
Protein Models

AbstractNearly all proteins interact specifically with other proteins, often forming reversible bound structures whose stability is critical to function. Proteins with BAR domains function to bind to, bend, and remodel biological membranes, where the dimerization of BAR domains is a key step in this function. Here we characterize the binding thermodynamics of homodimerization between the LSP1 BAR domain proteins in solution, using Molecular Dynamics (MD) simulations. By combining the MARTINI coarse-grained protein models with enhanced sampling through metadynamics, we construct a two-dimensional free energy surface quantifying the bound versus unbound ensembles as a function of two distance variables. Our simulations portray a heterogeneous and extraordinarily stable bound ensemble for these modeled LSP1 proteins. The proper crystal structure dimer has a large hydrophobic interface that is part of a stable minima on the free energy surface, which is enthalpically the minima of all bound structures. However, we also find several other stable nonspecific dimers with comparable free energies to the specific dimer. Through structure-based clustering of these bound structures, we find that some of these ‘nonspecific’ contacts involve extended tail regions that help stabilize the higher-order oligomers formed by BAR-domains, contacts that are separated from the homodimer interface. We find that the known membrane-binding residues of the LSP1 proteins rarely participate in any of the bound interfaces, but that both patches of residues are aligned to interact with the membrane in the specific dimer. Hence, we would expect a strong selection of the specific dimer in binding to the membrane. The effect of a 100mM NaCl buffer reduces the relative stability of nonspecific dimers compared to the specific dimer, indicating that it would help prevent aggregation of the proteins. With these results, we provide the first free energy characterization of interaction pathways in this important class of membrane sculpting domains, revealing a variety of interfacial contacts outside of the specific dimer that may help stabilize its oligomeric assemblies.

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 Improving The Performance Of The Amber Rna Force Field By Tuning The Hydrogen-Bonding Interactions

2018 ◽  
Author(s):  
Petra Kührová ◽  
Vojtěch Mlýnský ◽  
Marie Zgarbová ◽  
Miroslav Krepl ◽  
Giovanni Bussi ◽  
...  
Keyword(s):  
Md Simulations ◽  
Rna Motifs ◽  
Conformational Ensembles ◽  
Interaction Terms ◽  
Empirical Potentials ◽  
Hydrogen Bonding Interactions ◽  
Bonding Interaction ◽  
Free Energy Landscapes ◽  
Folding Simulations ◽  
Fine Tune

ABSTRACTMolecular dynamics (MD) simulations became a leading tool for investigation of structural dynamics of nucleic acids. Despite recent efforts to improve the empirical potentials (force fields,ffs), RNAffshave persisting deficiencies, which hamper their utilization in quantitatively accurate simulations. Previous studies have shown that at least two salient problems contribute to difficulties in description of free-energy landscapes of small RNA motifs: (i) excessive stabilization of the unfolded single-stranded RNA ensemble by intramolecular base-phosphate and sugar-phosphate interactions, and (ii) destabilization of the native folded state by underestimation of stability of base pairing. Here, we introduce a generalffterm (gHBfix) that can selectively fine-tune non-bonding interaction terms in RNAffs, in particular the H-bonds. gHBfix potential affects the pair-wise interactions between all possible pairs of the specific atom types, while all other interactions remain intact, i.e., it is not a structure-based model. In order to probe the ability of the gHBfix potential to refine theffnon-bonded terms, we performed an extensive set of folding simulations of RNA tetranucleotides and tetraloops. Based on these data we propose particular gHBfix parameters to modify the AMBER RNAff. The suggested parametrization significantly improves the agreement between experimental data and the simulation conformational ensembles, although our currentffversion still remains far from being flawless. While attempts to tune the RNAffsby conventional reparametrizations of dihedral potentials or non-bonded terms can lead to major undesired side effects as we demonstrate for some recently publishedffs, gHBfix has a clear promising potential to improve theffperformance while avoiding introduction of major new imbalances.

scholarly journals Accelerating Dissociative Events in Molecular Dynamics Simulations by Selective Potential Scaling

2019 ◽  
Author(s):  
Indrajit Deb ◽  
Aaron T. Frank
Keyword(s):  
Molecular Dynamics ◽  
Sampling Method ◽  
Potential Energy Function ◽  
Md Simulations ◽  
Cyclin Dependent Kinase ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Biologically Relevant ◽  
Dynamics Simulations ◽  
Dissociative Processes

ABSTRACTMolecular dynamics (or MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively “scaled” to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled-up ligand-water interactions in an attempt to increase the rate of ligand unbinding. By applying our selectively scaled MD (or ssMD) approach to three cyclin-dependent kinase 2 (CDK2)-inhibitor complexes, we were able to significantly accelerate ligand unbinding thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the unbinding as well as the binding free energies (∆Gsim) of the three inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers’-based rate extrapolation (KRE) method and a newly described free energy extrapolation (FEE) method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.

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