The broad goals of this project are the development of novel theoretical models and practical computational tools that will improve and facilitate the process of modeling and simulating bio-molecules. The new models will be based on """"""""implicit solvent"""""""" approach in which individual water molecules and mobile solvent ions are replaced by a continuous medium with the average properties of the solvent. Currently, the """"""""engine"""""""" of the methodology - responsible for the estimation of the key electrostatic interactions - is either the generalized Born (GB) or the Poisson Boltzmann model (PB). The GB model is computationally efficient, but lacks the critical accuracy of the fundamental, but computationally expensive PB approach. Within the proposed approach, exact solutions of the PB equation for typical molecular shapes will serve as the foundation for deriving computationally efficient, analytical models. The models will go beyond the current generation of the generalized Born (GB) models, in both accuracy and efficiency. New important features will be added, such as the ability to compute electrostatic potential at every point in space: potential generated by a bio-molecule is often a key determinant of its function. For large compounds, e.g. multi-protein complexes, viral capsids, the ribosome or the nucleosome, the proposed approach may be the only practical way to generate potential maps with the power of a desktop computer. Approaches specifically targeted to speed-up simulations based on the implicit solvent models will be developed. They will be based upon coarse-graining of the charge distribution and will not have the significant artifacts typical of the """"""""standard"""""""" schemes in which interactions beyond a specified distance are neglected. The methods will yield at least a 10-fold increase in computational speed for large bio-molecular structures. The use of the new models will be expanded to applications where the GB model is currently not applied, but where computational speed and accuracy are critical, for example in quantum mechanics-molecular mechanics (QM-MM) calculations on bio-molecules. The fast, analytical models of solvation will become more dependable. The models will be used to gain insights into the molecular mechanism of enhanced flexibility of short DNA fragments.

Public Health Relevance

Molecular modeling and simulations are nowadays indispensable tools in biomedical science and the drug discovery process. The proposed methods will significantly enhance their accuracy and speed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-Q (02))
Program Officer
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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Katkova, E V; Onufriev, A V; Aguilar, B et al. (2017) Accuracy comparison of several common implicit solvent models and their implementations in the context of protein-ligand binding. J Mol Graph Model 72:70-80
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 Model for Million-Atom Atomistic Simulations: Insights into the Organization of 30-nm Chromatin Fiber. J Chem Theory Comput 12:5946-5959
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; Tolokh, Igor S; Onufriev, Alexey V (2015) Accurate evaluation of charge asymmetry in aqueous solvation. J Phys Chem B 119:6092-100
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; 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

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