Machine Learning for Protein Function Prediction

Sihyun HAM 한국생물공학회 2017 한국생물공학회 학술대회 Vol.2017 No.4

Characterizing amyloid‐beta protein misfolding from molecular dynamics simulations with explicit water

Lee, Chewook,Ham, Sihyun Wiley Subscription Services, Inc., A Wiley Company 2011 Journal of computational chemistry Vol.32 No.2

<P><B>Abstract</B></P><P>Extracellular deposition of amyloid‐beta (Aβ) protein, a fragment of membrane glycoprotein called β‐amyloid precursor transmembrane protein (βAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Aβ protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all‐atom molecular dynamics simulations for physiological 42‐residue amyloid‐beta protein (Aβ42) in explicit water to characterize most plausible aggregation‐prone structure (APS) for the monomer and the very early conformational transitions for Aβ42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Aβ42 misfolding in water, the APS for Aβ42 monomer is characterized by the observed correlation between the nonlocal backbone H‐bond formation and the hydrophobic side‐chain exposure. Characteristics on the nature of the APS of Aβ42 allow us to provide new insight into the higher aggregation propensity of Aβ42 over Aβ40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Aβ42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Aβ42 aggregation process to cause AD. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011</P>

Conformational Entropy of Intrinsically Disordered Protein

Chong, Song-Ho,Ham, Sihyun American Chemical Society 2013 The Journal of physical chemistry B Vol.117 No.18

<P>Intrinsically disordered proteins (IDPs), though lacking stable tertiary structures, are known to possess a certain amount of residual structure. Conformational disorder plays a crucial role through the conformational entropy in regulating protein–protein and protein–ligand interactions involved in signaling and regulation, and also modulates protein aggregation and amyloidogenesis associated with a number of human diseases. However, a direct and quantitative connection between the residual structure and the conformational entropy remains to be established. Here we show using a novel computational approach that the conformational entropy of amyloid-beta protein, an IDP whose aggregation is associated with Alzheimer’s disease, is significantly correlated with the contents of the residual helical structure, β-sheet structure, and salt-bridge network. Identification of the thermodynamically significant residual structure is of fundamental importance for a comprehensive understanding of the relationship between the functional conformational disorder and the protein activity regulation, and will also serve the thermodynamic basis of the amyloid polymorphism.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpcbfk/2013/jpcbfk.2013.117.issue-18/jp401049h/production/images/medium/jp-2013-01049h_0005.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jp401049h'>ACS Electronic Supporting Info</A></P>

Thermodynamic-Ensemble Independence of Solvation Free Energy

Chong, Song-Ho,Ham, Sihyun American Chemical Society 2015 Journal of chemical theory and computation Vol.11 No.2

<P>Solvation free energy is the fundamental thermodynamic quantity in solution chemistry. Recently, it has been suggested that the partial molar volume correction is necessary to convert the solvation free energy determined in different thermodynamic ensembles. Here, we demonstrate ensemble-independence of the solvation free energy on general thermodynamic grounds. Theoretical estimates of the solvation free energy based on the canonical or grand-canonical ensemble are pertinent to experiments carried out under constant pressure without any conversion.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jctcce/2015/jctcce.2015.11.issue-2/ct500876x/production/images/medium/ct-2014-00876x_0002.gif'></P>

Protein Folding Thermodynamics: A New Computational Approach

Chong, Song-Ho,Ham, Sihyun American Chemical Society 2014 The Journal of physical chemistry B Vol.118 No.19

<P>Folding free energy is the fundamental thermodynamic quantity characterizing the stability of a protein. Yet, its accurate determination based on computational techniques remains a challenge in physical chemistry. A straightforward brute-force approach would be to conduct molecular dynamics simulations and to estimate the folding free energy from the equilibrium population ratio of the unfolded and folded states. However, this approach is not sensible at physiological conditions where the equilibrium population ratio is vanishingly small: it is extremely difficult to reliably obtain such a small equilibrium population ratio due to the low rate of folding/unfolding transitions. It is therefore desirable to have a computational method that solely relies on simulations independently carried out for the folded and unfolded states. Here, we present such an approach that focuses on the probability distributions of the effective energy (solvent-averaged protein potential energy) in the folded and unfolded states. We construct these probability distributions for the protein villin headpiece subdomain by performing extensive molecular dynamics simulations and carrying out solvation free energy calculations. We find that the probability distributions of the effective energy are well-described by the Gaussian distributions for both the folded and unfolded states due to the central limit theorem, which enables us to calculate the protein folding free energy in terms of the mean and the width of the distributions. The computed protein folding free energy (−2.5 kcal/mol) is in accord with the experimental result (ranging from −2.3 to −3.2 kcal/mol depending on the experimental methods).</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpcbfk/2014/jpcbfk.2014.118.issue-19/jp500269m/production/images/medium/jp-2014-00269m_0004.gif'></P>

Component analysis of the protein hydration entropy

Chong, Song-Ho,Ham, Sihyun Elsevier 2012 Chemical physics letters Vol.535 No.-

<P><B>Graphical abstract</B></P><P><ce:figure id='f0020'></ce:figure></P><P><B>Highlights</B></P><P>► A novel method is developed for the component analysis of the solvation entropy. ► This method enables microscopic interpretation of macroscopic thermodynamic data. ► Solvation entropy increases upon misfolding of amyloid-beta protein in water. ► This increase is mainly attributed to the formation of non-local backbone contacts.</P> <P><B>Abstract</B></P><P>We report the development of an atomic decomposition method of the protein solvation entropy in water, which allows us to understand global change in the solvation entropy in terms of local changes in protein conformation as well as in hydration structure. This method can be implemented via a combined approach based on molecular dynamics simulation and integral-equation theory of liquids. An illustrative application is made to 42-residue amyloid-beta protein in water. We demonstrate how this method enables one to elucidate the molecular origin for the hydration entropy change upon conformational transitions of protein.</P>

대학원생의 자기효능감, 스트레스, 폭력 경험, 경제적 환경, 관계갈등, 건강행위가 우울에 미치는 영향

김다혜(Kim, Da Hye),함옥경(Ham, Ok Kyung),서민희(Suh, Min Hee),박시현(Park, Sihyun) 한국보건간호학회 2021 韓國保健看護學會誌 Vol.35 No.1

Role of electrostatic interactions in determining the G-quadruplex structures

Lee, Jinkeong,Im, Haeri,Chong, Song-Ho,Ham, Sihyun Elsevier 2018 Chemical physics letters Vol.693 No.-

<P><B>Abstract</B></P> <P>We investigate the energetics of the antiparallel, hybrid and parallel type G-quadruplex structures of the human telomere DNA sequence. We find that both the conformational energy and solvation free energy of these structures are roughly inversely proportional to their radii of gyration. We rationalize this finding in terms of the dominance of the electrostatic contributions. We also show that the solvation free energy is more significant than the conformational energy in determining the G-quadruplex structures, which is in contrast to the canonical B-DNA structures. Our work will contribute to an understanding of the molecular mechanisms dictating various G-quadruplex topologies.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We investigate the energetics of three representative G-quadruplex structures. </LI> <LI> Conformational energy and solvation free energy correlate with the overall size. </LI> <LI> This can be rationalized by the dominance of the electrostatic interactions. </LI> <LI> Solvation free energy is more significant in determining the G-quadruplex stability. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

자녀의 초경 경험을 통한 어머니의 초경 경험 재구성 : Parse의 연구방법 적용

권진숙(Kwon, Jinsook),박시현(Park, Sihyun),함옥경(Ham, Okkyung),손민(Sohn, Min),이은진(Lee, Eun Jin),이재연(Lee, Jaeyeon) 한국보건간호학회 2021 韓國保健看護學會誌 Vol.35 No.2

Structural and ThermodynamicCharacteristics ThatSeed Aggregation of Amyloid-β Protein in Water

Chong, Song-Ho,Park, Mirae,Ham, Sihyun American Chemical Society 2012 Journal of chemical theory and computation Vol.8 No.2

<P>Amyloid-β (Aβ) proteins undergo conformationaltransitionsleading to aggregation-prone structures, which can initiate self-assemblyto form soluble oligomers and eventually insoluble amyloid fibrilswhen transferred from the transmembrane phase to the physiologicalaqueous phase. Yet, how Aβ proteins acquire an aggregation-pronenature during the conformational transitions in water remains elusive.Here, we investigate key structural and thermodynamic features ofa 42-residue Aβ (Aβ42) protein that seed aggregationbased on the fully atomistic, explicit-water molecular dynamics simulationsas well as on the integral-equation theory of liquids for solvationthermodynamic analysis. We performed a structure-based analysis onthe solvation free energy, a major determinant of the protein hydrophobicity/solubilitythat influences the aggregation propensity of Aβ42 protein inwater. In addition, the Gibbs free energy and its constituents includingprotein internal energy, protein configurational entropy, solvationenthalpy, and solvation entropy were computed to elucidate thermodynamicdriving forces for the conformational transitions of Aβ42 proteinin water. On the basis of the atomic-decomposition analysis of thesethermodynamic functions, we demonstrate how N-terminal (residues 1–11)and C-terminal (39–42) regions as well as the central region(16–18) contribute significantly to decreasing the solubilityof Aβ42 protein upon its conformational transitions in water.These results are consistent with the recent experimental and computationalimplications and further provide the molecular origin for why theC terminus may serve as an “internal seed” for aggregationand the N-terminal segment may act as a “catalyst” ininducing the Aβ42 self-assembly. This work takes a step forwardtoward the identification of structural and thermodynamic featuresof the Aβ42 monomer that seed the aggregation process in water.</P>