https://doi.org/10.1021/acs.jctc.5c00212
요약
- 온도 의존적인 IDP 상분리 모델 개발: 기존 CALVADOS 모델을 확장하여, LCST (Lower Critical Solution Temperature) 거동을 재현할 수 있는 온도 의존 coarse-grained 모델을 개발함. 이를 통해 IDP가 고온에서 응축하는 현상을 정량적으로 설명 가능해짐.
- 실험 기반 parameter fitting: 다양한 IDP 실험 데이터를 기반으로 side-chain 간 interaction strength를 온도 함수로 모델링, 실험과 시뮬레이션 결과 간의 정량적 일치를 달성함.
- sequence specificity 유지하며 온도 효과 반영: 모델은 각 아미노산 잔기의 상호작용 특이성을 유지하면서도 온도 증가에 따라 수용성 변화 및 상분리 임계점 이동을 잘 반영함.
- LCST 및 UCST 거동 모두 설명 가능: 온도에 따른 interaction strength 변화만 조정하면, UCST (Upper Critical Solution Temperature) 뿐 아니라 LCST 상분리 현상까지도 동시 설명 가능한 범용성 제공.
- 다양한 IDP에 적용 가능: FUS LCD, LAF-1 RGG, Ddx4 등 다양한 IDP에 대해 temperature-dependent binodal curves 예측 성공. 이는 LLPS 연구와 단백질 공학에 활용 가능성을 제시.
Abstract
Many intrinsically disordered proteins (IDPs) can undergo a liquid–liquid phase separation (LLPS) in water, depending on solution conditions (temperature, pH, and ionic strength). There are two types of LLPS that are controlled by temperature: those occurring above a lower critical solution temperature (LCST) and those occurring below an upper critical solution temperature (UCST). IDP coarse-grained (CG) models are particularly appropriate for investigating the physical and chemical factors that govern their LLPS and supramolecular organization. However, the development of CG models allowing simulations of both LCST and UCST behavior of temperature-sensitive IDPs is still in its infancy. In this context, we present here a novel temperature-dependent (TD) CG model for IDP simulations based on the MARTINI 3 force field. The model was developed by modifying the Lennard–Jones potentials between apolar or charged solute beads and water with a TD rescaling factor. It was parametrized to fit the TD potentials of mean force (PMF) between two apolar or two charged molecules computed using all-atom (AA) simulations. We show that the TD CG model is able to reproduce the experimentally known LLPS of both LCST and UCST low-complexity sequences and to estimate phase transition temperatures comparable to experimental measurements.