Non-bonded force field model with advanced restrained electrostatic potential charges (RESP2)

Schauperl, Michael; Nerenberg, Paul S.; Jang, Hyesu; Wang, Lee‐Ping; Bayly, Christopher I.; Mobley, David L.; Gilson, Michael K.

doi:10.1038/s42004-020-0291-4

Cited by 179 publications

(162 citation statements)

References 83 publications

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“…In the second step, equivalent charges are generated at freely rotating methyl groups, and the charges at non-hydrogen atoms are reduced until the modifications start to affect the overall fit. The described process is known as the restrained fitting of electrostatic potential [ 104 ]. Since the final model is constructed using non-iterative, modular parameterization, it can be adjusted by modifying the current steps or adding new into the established protocol.…”

Section: Computational Simulations Of Macrolide Interactionsmentioning

confidence: 99%

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Jednačak

Mikulandra

Novak

2020

IJMS

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Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed.

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Section: Computational Simulations Of Macrolide Interactionsmentioning

confidence: 99%

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Jednačak

Mikulandra

Novak

2020

IJMS

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“…Much molecular modeling uses classical fixed-charge force fields without an explicit accounting for polarization [31]. Such two-body additive force fields are implicitly polarized to hopefully match a level of polarization appropriate on average for condensed-phase simulations [32][33][34]. This is true for common force fields in the AMBER, CHARMM, GROMOS and OPLS families (e.g.…”

Section: Polarization Can Potentially Pose Particular Challengesmentioning

confidence: 99%

SAMPL7 Challenge Overview: Assessing the Reliability of Polarizable and Non-Polarizable Methods for Host-Guest Binding Free Energy Calculations

Amezcua¹,

Mobley²

2020

Preprint

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The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories -- a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of a two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.

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“…This has recently been shown to be the case for RESP partial charges. 71 Lennard-Jones parameter optimization is an active area of research 72,73 7 Conclusions and Recommendations…”

Section: Non-coulombic Ff Parametersmentioning

confidence: 99%

A Simple Method for Including Polarization Effects in Solvation Free Energy Calculations When Using Fixed-Charge Force Fields: Alchemically Polarized Charges.

Kelly

Smith²

2020

Preprint

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<div><div>The incorporation of polarizability in classical force-field molecular simulations is an ongoing area of research. We focus here on its application to hydration free energy simulations of organic molecules. In contrast to computationally complex approaches involving the development of explicitly polarizable force fields, we present herein a simple methodology for incorporating polarization into such simulations using standard fixed-charge force-fields, which we call the Alchemically Polarized Charges (APolQ) method. APolQ employs a standard classical alchemical free energy change simulation to calculate the free energy difference between a fully polarized solute particle in a condensed phase and its unpolarized state in a vacuum. One electronic structure (ES) calculation to of the electron densities is required for each state: for the former, we use a Polarizable Continuum Model (PCM), and for the latter we use vacuum-phase electronic structure calculations.</div><div><br></div><div>We applied APolQ to hydration free energy data for a test set of 45 neutral solute molecules in the FreeSolv database, and compared results obtained using three different water models (SPC/E, TIP3P, OPC3) and using MBIS and RESP partial charge methodologies. ES calculations were carried out at the MP2 level of theory and with cc-pVTZ and aug-cc-pVTZ basis sets. In comparison with AM1-BCC, we found that APolQ outperforms it for the test set. Despite our method using default GAFF parameters, the MBIS partial charges yield Absolute Average Deviations (AAD) 1.5 to 1.9 kJ·mol<sup>−1</sup> lower than AM1-BCC.</div><div><br></div><div>We conjecture that this method can be further improved by fitting the Lennard-Jones and torsional parameters to partial charges derived using MBIS or RESP methodologies. </div></div>

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Non-bonded force field model with advanced restrained electrostatic potential charges (RESP2)

Cited by 179 publications

References 83 publications

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

SAMPL7 Challenge Overview: Assessing the Reliability of Polarizable and Non-Polarizable Methods for Host-Guest Binding Free Energy Calculations

A Simple Method for Including Polarization Effects in Solvation Free Energy Calculations When Using Fixed-Charge Force Fields: Alchemically Polarized Charges.

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