# Minimal Collective Variables for Conformational Transitions in Steered and Temperature-Accelerated MD Simulations: A T4 Lysozyme Case Study

## TL;DR

This study identifies minimal collective variables to drive conformational transitions in T4 lysozyme using steered and temperature-accelerated MD simulations.

## Contribution

A minimal set of collective variables is identified for successful conformational transitions in T4 lysozyme using SMD and TAMD.

## Key findings

- CVs at both large and small scales are necessary for successful transitions in T4 lysozyme.
- A salt bridge between Arg8 and Glu64 stabilizes the closed state and must break for hinge bending.
- Phe4 reorients to a hydrophobic pocket to stabilize the open state.

## Abstract

Conformational transitions in proteins can be difficult
to observe
with equilibrium molecular dynamics and challenging for enhanced sampling
methods like Targeted MD when high-resolution structural data are
unavailable. Low-resolution data, such as interatomic distances and
angles, can serve as collective variables (CVs) to bias steered MD
(SMD) simulations, but the optimal choice and number of CVs remain
unclear. Here, we identify a minimal set of CVs that drive successful
transitions between metastable states in T4 lysozyme. We validate
them using temperature-accelerated MD (TAMD) to accelerate conformational
changes in the absence of target bias. We found that CVs at both the
largest and smallest scales are necessary, including interdomain hinge
bending and local side-chain reorientation. A salt bridge between
Arg8 and Glu64 stabilizes the closed state and must break for hinge
bending, while Phe4 reorients to a hydrophobic pocket to stabilize
the open state. Our results highlight the importance of selecting
appropriate CVs and optimizing the steering protocol to prevent protein
deformation. This work demonstrates that SMD simulations can serve
as a predictive tool for understanding protein conformational changes
in the absence of high-resolution structural data.