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Petersen, Andrew Alva (2006) pH-DEPENDENT FREE ENERGY CALCULATIONS FOR EXPLICIT SOLVENT MOLECULAR DYNAMICS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Designing drugs for treating diseases is one of the main motivations for understanding how proteins are able to recognize their substrates. Recent growth in computational power has encouraged the use of numerical tools like atomic detailed molecular dynamics for investigating proteins. Until recently, atomic detail molecular dynamics did not allow for the transfer of protons in the solute or solvent of the model during dynamics. Modeling this transfer in the protein is important because there are seven titratable amino acids. This means that they can exist in different protonation states or states of charge. The most important titratable sites are usually deeply buried. Several methods are available for doing proton dynamics for the titratable amino acids of the solute. Unfortunately deeply buried sites challenge available methods because the models need to capture the hydrophobic effect of buried regions, the hydrophilic effect of solvent penetration and the subtlety of charged networks. These effects sometimes assist, compete, or balance each other. One solution for the above challenges is to exploit the accuracy that comes with a full atomic detailed explicitly solvated model. However such an approach runs into problems because protonation state changes at 300K require unreasonably long simulations due to solvent reorientation relaxation times. As a result, currently available methods compromise the atomic detail description in some way, either by using continuum protonation states, by using continuum solvent, or by stepping back from the atomic detail description. Our method uses both discrete protonation states and atomic detail explicit solvent. The water orientation problem is overcome by using elevated temperatures, and the information from a wide range of temperatures, including those at 300K, are woven together with our Weighted Histogram algorithm. This then gives us an accurate density of states, from which we can calculate a full range of thermodynamic results. We used our methods to calculate the Bond Dissociation Energy (BDE) of the H-S bond in the solvated single site Cysteine system. This calculated BDE for Cysteine = 90.3-+1 kcal/mole. We have found this number agrees to within 3% of the experimental BDE of a very similar bond in thiomethane, H-SCH3. The experimental BDE for the H-S bond in thio-methane is 88-+1 kcals/mole. This is very good agreement and is some validation of our methods.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Petersen, Andrew Alvaaapst12@pitt.eduAAPST12
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoskies,
Committee MemberZuckerman, Danieldmz@ccbb.pitt.eduDDMMZZ
Committee MemberJasnow, Daviddmj@pitt.eduDMJ
Committee MemberRosenberg, John Mjmr@jmr3.xtal.pitt.eduROSENBRG
Committee MemberSwendsen, Robert
Committee MemberWu, X. Lxlwu@pitt.eduXLWU
Date: 29 September 2006
Date Type: Completion
Defense Date: 5 June 2006
Approval Date: 29 September 2006
Submission Date: 10 October 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Physics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Constant pH Simulation; Monte Carlo; WHAM; Molecular Dynamics; Proton Dynamics; Simulated Annealing; Weighted Histograms
Other ID:, etd-10102005-222726
Date Deposited: 10 Nov 2011 20:02
Last Modified: 15 Nov 2016 13:50


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