구글 알파폴드, 인공지능이 과학기술의 패러다임을 바꾼다

석차옥 대우재단 2021 지식의 지평 Vol.- No.31

콜로니 에너지를 이용한 단백질-리간드 결합 문제에서의 엔트로피 효과 계산

이주용,석차옥,Lee, Ju-Yong,Seok, Cha-Ok 한국생물정보시스템생물학회 2006 Bioinformatics and Biosystems Vol.1 No.2

단백질-리간드 결합 예측은 새로운 신약 선도 물질을 발견하고 최적화 하는데 있어서 중요한 도구로 널리 사용되고 있다. 결합의 정확도는 일반적으로 각 결합 계산에서 사용되는 평가 함수(scoring function)에 따라 결정된다. 평가 함수는 그 함수가 가지고 있는 기력 가정에 따라 force-field based, empirical, knowledge-based의 세 가지로 분류할 수 있다. 이 중에서 force-field based 함수는 물리적인 상호작용을 가장 구체적으로 기술한다. 그러나 현재 제시된 대부분의 force-field based 함수들은 분산력과 정전기적인 힘 등의 에너지만을 고려할 뿐 엔트로피의 영향을 포함하지 않는 단점을 가지고 있다. 본 논문에서는 force-field based 평가 함수를 이용하는 경우 기존의 도킹 프로그램이 생성해 내는 구조 정보를 활용하여, 엔트로피를 고려할 수 있는 방법을 제시한다. 또한 이 방법을 DOCK 평가 함수에 적용시켰을 때 decoy discrimination에서 향상된 결과를 얻어낼 수 있음을 보였다. 이는 더 정확한 도킹 계산이 가능함을 의미한다. Computational prediction of protein-ligand binding has been widely used as a tool to discover lead compounds fur new drugs. Prediction accuracy is determined in part by the scoring function used in docking calculations. Diverse scoring functions are available, and these can be classified into force-field based, empirical, and knowledge-based functions depending upon the basic assumptions made in development. Among these, force-field based functions consider physical interactions the most in detail. However, the force-field based functions have the drawback of not including the entropic effect while considering only the energy contribution such as dispersion or electrostatic forces. In this article, a method to take into account of the entropic effect using the colony energy is suggested when force-field based scoring functions is used by extracting conformational information obtained from the pre-existing docking program. An improved result for decoy discrimination is illustrated when the method is applied to the DOCK scoring function, and this implies that more accurate docking calculation is possible.

Structural Basis of Functional Conversion of a Floral Repressor to an Activator: A Molecular Dynamics Simulation Study

Sukki Kang,석차옥,Juyong Lee,Myeong Sup Lee 대한화학회 2008 Bulletin of the Korean Chemical Society Vol.29 No.2

FLOWERING LOCUS T (FT) and TERMINAL FLOWER 1 (TFL1) in Arabidopsis are homologous proteins that perform opposite functions: FT is an activator of flowering, and TFL1 is a repressor. It was shown before that change of a single amino acid (His88) of TFL1 to the corresponding amino acid (Tyr) of FT is enough to convert the floral repressor to an activator. However, structural basis of the functional conversion has not been understood. In our molecular dynamics simulations on modified TFL1 proteins, a hydrogen bond present in native TFL1 between the His88 residue and a residue (Asp144) in a neighboring external loop became broken by change of His88 to Tyr. This breakage induced conformational change of the external loop whose structure was previously reported to be another key functional determinant. These findings reveal that the two important factors determining the functional specificities of the floral regulators, the key amino acid (His88) and the external loop, are correlated, and the key amino acid determines the functional specificity indirectly by affecting the conformation of the external loop.

Conformational Sampling of Flexible Ligand-binding Protein Loops

이규리,신웅희,박한범,신석민,석차옥 대한화학회 2012 Bulletin of the Korean Chemical Society Vol.33 No.3

Protein loops are often involved in diverse biological functions, and some functional loops show conformational changes upon ligand binding. Since this conformational change is directly related to ligand binding pose and protein function, there have been numerous attempts to predict this change accurately. In this study, we show that it is plausible to obtain meaningful ensembles of loop conformations for flexible, ligand-binding protein loops efficiently by applying a loop modeling method. The loop modeling method employs triaxial loop closure algorithm for trial conformation generation and conformational space annealing for global energy optimization. When loop modeling was performed on the framework of ligand-free structure, loop structures within 3 RMSD from the crystal loop structure for the ligand-bound state were sampled in 4 out of 6 cases. This result is encouraging considering that no information on the ligand-bound state was used during the loop modeling process. We therefore expect that the present loop modeling method will be useful for future developments of flexible protein-ligand docking methods.

Prediction of Protein Structure and Interaction by GALAXY Protein Modeling Programs

신웅희,이규리,허림,이하섭,석차옥 한국구조생물학회 2014 Biodesign Vol.2 No.1

In this review, recently developed GALAXY protein modeling programs are introduced and advantages and disadvantagesof these programs for both program users and method developers are discussed. The GALAXY package consists of thetemplate-based modeling program GalaxyTBM, the loop/terminus modeling program GalaxyLoop, the model refinementprogram GalaxyRefine, the homo-oligomer prediction program GalaxyGemini, and the protein-ligand docking programGalaxyDock. These programs have been tested with some success in community-wide competition Critical Assessmentof Techniques for Protein Structure Prediction (CASP) experiments. For the development of these programs, modelingproblems have been posed as global optimization problems of designed energy functions. The free energy functionsof GALAXY have been carefully designed by combining physical chemistry principles and structure and sequenceinformation. Efficient conformational search methods such as conformational space annealing and triaxial loop closurehave been employed. Freely accessible web servers of the modeling programs are available at http://galaxy.seoklab.org,and some programs can be downloaded from http://galaxy.seoklab.org/softwares.

Protein Loop Modeling Using Fragment Assembly

Dong-seon Lee,석차옥,이주련 한국물리학회 2008 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.52 No.4

We model loop regions of proteins based on a fragment assembly method. The fragments that comprise candidates of the local structure of a protein loop are collected from a structure database, and all loop conformations possible from a smooth assembly of the fragments are generated. For each of the fragment-assembled conformations, a Monte Carlo simulation in the conformational subspace that satisfies the loop closure constraint is performed to minimize the root-mean-square deviation of the backbone dihedral angles from the fragment angles. The side-chains are then built using a rotamer library, and the backbone and the side-chain conformations are optimized locally with the AMBER 96 force field without solvation terms to remove steric clashes. The resulting conformations are then ranked using the DFIRE potential. A test prediction for eight protein loops with sizes ranging from 8 to 12 residues is presented to show the feasibility of our method. Tests with further optimization using Monte Carlo with minimization show that extensive conformational optimization leading to deviation from the original fragment-assembled structures tend to deteriorate the prediction accuracy, suggesting that the utilization of fragment information is superior to purely energy-based methods.

Molecular evolution of ACTIN RELATED PROTEIN 6, a component of SWR1 complex in Arabidopsis

서은주,박철민,최규하,이동선,석차옥,이일하 한국식물학회 2016 Journal of Plant Biology Vol.59 No.5

To date, it has been assumed that the evolution of a protein complex is different from that of other proteins. However, there have been few evidences to support this assumption. To understand how protein complexes evolve, we analyzed the evolutionary constraints on ACTIN RELATED PROTEIN 6 (ARP6), a component of the SWR1 complex. Interspecies complementation experiments using transgenic plants that ectopically express transARP6s (ARP6s from other organisms) showed that the function of ARP6s is conserved in plants. In addition, a yeast two-hybrid analysis revealed that this functional conservation depends on its ability to bind with both PIE1 and AtSWC6. ARP6 consists of 4 domains similar to actin. Functional analysis of chimericARP6s (domain-swapped ARP6s between Arabidopsis and mouse) demonstrated that each domain of ARP6s imposes differential evolutionary constraints. Domains 1 and 3 of ARP6 were found to interact with SWC6 and PIE1, respectively, and domain 4 provides a nuclear localization signal. Moreover, domains 1 and 3 showed a slower evolution rate than domain 4, indicating that the interacting domains have higher evolutionary constraints than non-interacting domains do. These findings suggest that the components of this protein complex have evolved coordinately to preserve their interactions.

Contribution of Counterion Entropy to the Salt-Induced Transition Between B-DNA and Z-DNA

Youn-Kyoung Lee,Juyong Lee,Jung Hyun Choi,석차옥 대한화학회 2012 Bulletin of the Korean Chemical Society Vol.33 No.11

Formation of Z-DNA, a left-handed double helix, from B-DNA, the canonical right-handed double helix, occurs during important biological processes such as gene expression and DNA transcription. Such B-Z transitions can also be induced by high salt concentration in vitro, but the changes in the relative stability of BDNA and Z-DNA with salt concentration have not been fully explained despite numerous attempts. For example, electrostatic effects alone could not account for salt-induced B-Z transitions in previous studies. In this paper, we propose that the B-Z transition can be explained if counterion entropy is considered along with the electrostatic interactions. This can be achieved by conducting all-atom, explicit-solvent MD simulations followed by MM-PBSA and molecular DFT calculations. Our MD simulations show that counterions tend to bind at specific sites in B-DNA and Z-DNA, and that more ions cluster near Z-DNA than near B-DNA. Moreover, the difference in counterion ordering near B-DNA and Z-DNA is larger at a low salt concentration than at a high concentration. The results imply that the exclusion of counterions by Z-DNA-binding proteins may facilitate Z-DNA formation under physiological conditions.