The proposed research, which is purely theoretical and computational, has three main parts, all focused on aspects of the phenomenon of molecular recognition, which is of basic and practical importance in biology and medicine. The first part concerns miniature receptor molecules, called hosts, which are used today to stabilize and deliver many drugs and which also show promise as medications in their own right. We plan to provide other scientists with new, tested software to help them design these miniature receptors and thereby speed the development of new medications. We also plan to carry out simulations of these molecules in order to develop a better understanding of how they work and also to gain insight into how larger receptors, such as many proteins, bind drugs. The second part is to study the changes in entropy that occur when molecules bind. In recent work, we have found that changes in entropy associated with the motions of receptors and the molecules they bind (ligands) can have a surprisingly strong influence on how tightly they bind each other. However, we do not yet understand these entropy changes well enough to make them work in our favor when designing tight-binding receptors and ligands. We plan to further develop our method of computing these entropy changes from computer simulations, and then use the method to develop a better understanding of them. For example, we would like to be able to predict when modifying a ligand to make it more rigid, and therefore lower in entropy, will increase its affinity. In addition, we plan to incorporate the new entropy calculations into software for computing binding affinities which we hope will help researchers design new drugs. The third part is to develop a new idea of applying the concept of stress to molecular biophysics. Materials scientists have come up with equations for computing the stress in a material from an atomistic computer simulation, and we think these equations can tell us something useful about how hosts, proteins and other molecules work. For one thing, we hypothesize that if receptor- ligand binding produces localized stress, then modifying the ligand to reduce this stress might increase the binding affinity. Thus, computing stress might help with the design of tight-binding ligands. We also hypothesize that, when a ligand binds an allosteric protein, a protein whose conformation shifts on binding, the mechanism of the shape change involves propagation of a wave of stress from the binding site. If we can understand how proteins change conformation, this would help us to re-engineer them for medical and industrial uses.

Public Health Relevance

This project applies chemical theory and computer modeling to the phenomenon of molecular recognition. Our overall goal is to develop a better understanding of what makes specific molecules bind each other, and to incorporate this understanding into software that will be useful in protein engineering and the design of new medications.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter C
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University of California San Diego
Schools of Pharmacy
La Jolla
United States
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Wickstrom, Lauren; Deng, Nanjie; He, Peng et al. (2016) Parameterization of an effective potential for protein-ligand binding from host-guest affinity data. J Mol Recognit 29:10-21
Yin, Jian; Henriksen, Niel M; Slochower, David R et al. (2016) The SAMPL5 host-guest challenge: computing binding free energies and enthalpies from explicit solvent simulations by the attach-pull-release (APR) method. J Comput Aided Mol Des :
Yin, Jian; Henriksen, Niel M; Slochower, David R et al. (2016) Overview of the SAMPL5 host-guest challenge: Are we doing better? J Comput Aided Mol Des :
Li, Amanda; Voronin, Alexey; Fenley, Andrew T et al. (2016) Evaluation of Representations and Response Models for Polarizable Force Fields. J Phys Chem B 120:8668-84
Yin, Jian; Fenley, Andrew T; Henriksen, Niel M et al. (2015) Toward Improved Force-Field Accuracy through Sensitivity Analysis of Host-Guest Binding Thermodynamics. J Phys Chem B 119:10145-55
Henriksen, Niel M; Fenley, Andrew T; Gilson, Michael K (2015) Computational Calorimetry: High-Precision Calculation of Host-Guest Binding Thermodynamics. J Chem Theory Comput 11:4377-94
Gao, Kaifu; Yin, Jian; Henriksen, Niel M et al. (2015) Binding enthalpy calculations for a neutral host-guest pair yield widely divergent salt effects across water models. J Chem Theory Comput 11:4555-64
Muddana, Hari S; Yin, Jian; Sapra, Neil V et al. (2014) Blind prediction of SAMPL4 cucurbit[7]uril binding affinities with the mining minima method. J Comput Aided Mol Des 28:463-74
Muddana, Hari S; Sapra, Neil V; Fenley, Andrew T et al. (2014) The SAMPL4 hydration challenge: evaluation of partial charge sets with explicit-water molecular dynamics simulations. J Comput Aided Mol Des 28:277-87
Li, Amanda; Muddana, Hari S; Gilson, Michael K (2014) Quantum Mechanical Calculation of Noncovalent Interactions: A Large-Scale Evaluation of PMx, DFT, and SAPT Approaches. J Chem Theory Comput 10:1563-1575

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