Progress in modern bio-molecular sciences, from structural biology to structure-based drug design, is greatly accelerated by methods of atomic-level modeling and simulations that bridge the gap between theory and experiment. One of the widely used methods of this kind, the so-called implicit solvation, provides significant computational advantages and versatility by representing the effects of solvent - often the most computationally expensive part of such simulations - in an approximate manner, via a continuum. Currently, the practical "engine''of this implicit solvation methodology is either the generalized Born (GB) model or the more fundamental formalism of the Poisson (or Poisson-Boltzmann) equation. It is the relatively much simpler and more efficient GB model that has almost exclusively been used in molecular dynamics (MD) simulations where it has shown impressive success in a variety of areas, from protein folding to molecular docking. However, the much greater computational efficiency and versatility of such approximate models are currently accompanied with a reduced accuracy relative to the more traditional, but computationally very demanding explicit solvent approach. These accuracy limitations must be addressed in order to fully utilize the numerous benefits offered by the implicit solvation models in molecular simulations. In addition, the speed limitations of these models have also become apparent lately, and need to be overcome. During the period of previous funding, we have developed new models of implicit aqueous solvation that are more accurate and efficient than the popular GB models currently in use by the bio-molecular modeling community. The new models directly address the well-known deficiencies of the canonical GB models, such as secondary structure bias or erroneous salt-bridge strength, present in the very GB framework that remained unchanged over the past 20 years. A combination of novel approaches promises to speed-up MD simulations based on our implicit solvation models by up to 4 orders of magnitude. For the modeling community to benefit from these developments, the methods must be carefully implemented, tested, and further refined specifically in the context of Molecular Dynamics simulations where they are expected to make the highest impact. This renewal thus aims to incorporate the new models into freely available as well as popular Molecular Dynamics simulation packages. Our goals in this regard will be, first to improve the accuracy of MD simulations applied to bio-molecular systems, and second, to improve their speed. A third, forward looking goal will be to develop a conceptually new analytical framework of aqueous solvation that goes beyond the current foundation of practical analytical electrostatic models -- the Poisson formalism of continuum, linear, local response electrostatics. The proposed fully implicit, analytical models will retain most of the solvation effects of the first hydration shell.

Public Health Relevance

Molecular modeling and simulations are indispensable tools in biomedical science and the drug discovery process. The proposed research will significantly enhance the capabilities of these tools and the likelihood of important discoveries by making them faster, more accurate, and more widely available.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Lyster, Peter
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Virginia Polytechnic Institute and State University
Biostatistics & Other Math Sci
Schools of Engineering
United States
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Izadi, Saeed; Onufriev, Alexey V (2016) Accuracy limit of rigid 3-point water models. J Chem Phys 145:074501
Izadi, Saeed; Anandakrishnan, Ramu; Onufriev, Alexey V (2016) Implicit Solvent Simulation of Million-Atom Structures: Insights into the Organization of 30-nm Chromatin Fiber. J Chem Theory Comput :
Anandakrishnan, Ramu; Drozdetski, Aleksander; Walker, Ross C et al. (2015) Speed of conformational change: comparing explicit and implicit solvent molecular dynamics simulations. Biophys J 108:1153-64
Mukhopadhyay, Abhishek; Tolokh, Igor S; Onufriev, Alexey V (2015) Accurate evaluation of charge asymmetry in aqueous solvation. J Phys Chem B 119:6092-100
Izadi, Saeed; Aguilar, Boris; Onufriev, Alexey V (2015) Protein-Ligand Electrostatic Binding Free Energies from Explicit and Implicit Solvation. J Chem Theory Comput 11:4450-9
Mukhopadhyay, Abhishek; Aguilar, Boris H; Tolokh, Igor S et al. (2014) Introducing Charge Hydration Asymmetry into the Generalized Born Model. J Chem Theory Comput 10:1788-1794
Onufriev, Alexey V; Aguilar, Boris (2014) Accuracy of continuum electrostatic calculations based on three common dielectric boundary definitions. J Theor Comput Chem 13:
Onufriev, Alexey V; Alexov, Emil (2013) Protonation and pK changes in protein-ligand binding. Q Rev Biophys 46:181-209
Savin, Alexander V; Kikot, Irina P; Mazo, Mikhail A et al. (2013) Two-phase stretching of molecular chains. Proc Natl Acad Sci U S A 110:2816-21
Anandakrishnan, Ramu; Baker, Charles; Izadi, Saeed et al. (2013) Point charges optimally placed to represent the multipole expansion of charge distributions. PLoS One 8:e67715

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